Triazolyl pyridyl benzenesulfonamides

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR2 or CCR9 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2 and CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, CCR9-mediated diseases, as controls in assays for the identification of CCR2 antagonists and as controls in assays for the identification of CCR9 antagonists.

RELATED APPLICATIONS

This application claims priority to U.S. provisional application Ser.No. 60/831,042 filed Jul. 14, 2006. The disclosure of this priorityapplication is incorporated herein in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The present invention described herein was supported at least in part byNIH (U19-AI056690-01). The government may have certain rights in theinvention.

BACKGROUND

The present invention provides compounds, pharmaceutical compositionscontaining one or more of those compounds or their pharmaceuticallyacceptable salts, which are effective in inhibiting the binding orfunction of various chemokines to chemokine receptors. As antagonists ormodulators of chemokine receptors, the compounds and compositions haveutility in treating various immune disorder conditions and diseases.

Chemokines, also known as chemotactic cytokines, are a group of smallmolecular-weight proteins that are released by a wide variety of cellsand have a variety of biological activities. Chemokines attract varioustypes of cells, of the immune system, such as macrophages, T cells,eosinophils, basophils and neutrophils, and cause them to migrate fromthe blood to various lymphoid and none-lymphoid tissues. They mediateinfiltration of inflammatory cells to sites of inflammation, and areresponsible for the initiation and perpetuation of many inflammationdiseases (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall et al.,Curr. Opin. Immunol., 6:865-873 (1994)).

In addition to stimulating chemotaxis, chemokines can induce otherchanges in responsive cells, including changes in cell shape, granuleexocytosis, integrin up-regulation, formation of bioactive lipids (e.g.,leukotrienes), respiratory burst associated with leukocyte activation,cell proliferation, resistance to induction of apoptosis andangiogenesis. Thus, chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation. They are alsostimulators of a multitude of cellular processes that bear importantphysiological functions as well as pathological consequences.

Chemokines exert their effects by activating chemokine receptorsexpressed by responsive cells. Chemokine receptors are a class ofG-protein coupled receptors, also known as seven-transmembranereceptors, found on the surface of a wide variety of cell types such asleukocytes, endothelial cells, smooth muscle cells and tumor cells.

Chemokines and chemokine receptors are expressed by intrinsic renalcells and infiltrating cells during renal inflammation (Segerer et al.,J. Am. Soc. Nephrol., 11:152-76 (2000); Morii et al., J. DiabetesComplications, 17:11-5 (2003); Lloyd et al. J. Exp. Med., 185:1371-80(1997); Gonzalez-Cuadrado et al. Clin. Exp. Immunol, 106:518-22 (1996);Eddy & Giachelli, Kidney Int., 47:1546-57 (1995); Diamond et al., Am. J.Physiol., 266:F926-33 (1994)). In humans, CCR2 and ligand MCP-1 areamong the proteins expressed in renal fibrosis, and are correlated withthe extent of macrophage infiltration into the interstitium (Yang etal., Zhonghua Yi Xue Za Zhi, 81:73-7 (2001); Stephan et al., J. Urol.,167:1497-502 (2002); Amann et al., Diabetes Care, 26:2421-5 (2003); Daiet al., Chin. Med. J. (Engl), 114:864-8 (2001)). In animal models ofrenal fibrosis, blockade of CCR2 or MCP-1 leads to a marked reduction inseverity of renal inflammation (Kitagawa et al., Am. J. Pathol.,165:237-46 (2004); Wada et al., Am. J. Pathol., 165:237-46 (2004);Shimizu et al., J. Am. Soc. Nephrol., 14:1496-505 (2003)).

Rheumatoid arthritis is a chronic disease of the joints characterized bysynovial inflammation that leads to the destruction of cartilage andbone. Although the underlying causes of the disease are unknown, it isbelieved that macrophages and Th-1 type T cells play a key role in theinitiation and perpetuation of the chronic inflammatory process(Vervoordeldonk et al., Curr. Rheumatol. Rep., 4:208-17 (2002)).

MCP-1 is among the several chemokines, including MIP-1α and IL-8,identified in rheumatoid synovium (Villiger et al., J. Immunol.,149:722-7 (1992); Scaife et al., Rheumatology (Oxford), 43:1346-52(2004); Shadidi et al., Scand. J. Immunol., 57:192-8 (2003); Taylor etal., Arthritis Rheum., 43:38-47 (2000); Tucci et al., Biomed. Sci.Instrum., 34:169-74 (1997)). Chemokine receptors CCR1, CCR2, CCR3 andCCR5 are up-regulated in the joints from arthritic mice (Plater-Zyberket al., Immunol. Lett., 57:117-20 (1997). Blockade of MCP-1 activityusing a CCR2 antagonist or an antibody against MCP-1 have been shownefficacious in reducing joint inflammation in experimental models ofrheumatoid arthritis (Gong et al., J. Exp. Med., 186:131-7 (1997); Ogataet al., J. Pathol., 182:106-14 (1997)).

Chemokine receptor-mediated infiltration of macrophages in the fattissues may also contribute to the complications arising from obesity, acondition resulting from excessive storage of fat in the body. Obesitypredisposes the affected individuals to many disorders, such asnon-insulin-dependent diabetes, hypertension, stroke, and coronaryartery disease. In obesity, adipose tissues have altered metabolic andendocrine functions that lead to an increased release of fatty acids,hormones, and pro-inflammatory molecules. Adipose tissue macrophages arebelieved to be a key source of pro-inflammatory cytokines includingTNF-alpha, iNOS and IL-6 (Weisberg et al., J. Clin. Invest.,112:1796-808 (2003)). Recruitment of macrophages to the adipose tissueis likely mediated by MCP-1 produced by adipocytes (Christiansen T, etal., Int J Obes (Lond). 2005 January; 29(1):146-50; Sartipy et al.,Proc. Natl. Acad. Sci. U.S.A., 100:7265-70 (2003)).

Elevated MCP-1 may induce adipocyte differentiation and insulinresistance, and contribute to pathologies associated withhyper-insulinemia and obesity. MCP-1 is over-expressed in plasma inobese mice compared to lean controls and white adipose is a majorsource. MCP-1 has also been shown to accelerate wound healing, and has adirect angiogenic effect on epithelial cells, and may play a direct rolein the remodeling of adipose tissue in obesity. (Sartipy P, Loskutoff DJ., Proc, Natl. Acad. Sci. U.S.A., 100:7265 (2003)).

MCP-1 plasma levels are substantially increased in Diet Induce Obesity(DIO) mice, and a strong correlation between plasma MCP-1 levels andbody weight has been identified. Furthermore, elevation of MCP-1 inducedby high fat diet causes changes in the CD11b positive monocytepopulation in DIO mice. (Takahashi K, et al., J. Biol. Chem., 46654(2003)).

Furthermore, chronic inflammation in fat is thought to play a crucialrole in the development of obesity-related insulin resistance (Xu H. etal., J Clin Invest. 2003 December; 112(12):1821-30). It has beenproposed that obesity related insulin resistance is, at least in part, achronic inflammatory disease initiated in adipose tissue, Manyinflammation and macrophage specific genes are dramatically upregulatedin white adipose tissue in mouse models of genetic and high fatdiet-induced obesity (DIO), and this upregulation precedes a dramaticincrease in circulating insulin.

Increased expression levels of monocyte CCR2 and monocytechemoattractant protein-1 in patients with diabetes mellitus(Biochemical and Biophysical Research Communications, 344(3):780-5(2006)) were found in a study involving diabetic patients. Serum MCP-1concentrations and surface expression of CCR2 on monocytes in diabeticpatients were significantly higher than in non-diabetics, and the serumMCP-1 levels correlated with HbA1c, triglycerides, BMI, hs-CRP. Surfaceexpression levels of CD36 and CD68 on monocytes were significantlyincreased in diabetic patients and more unregulated by MCP-1 indiabetics, augmenting uptake of ox-LDL, and hence potentially foam celltransformation. Elevated serum MCP-1 and increased monocyte CCR2, CD36,CD68 expression correlated with poor blood glucose control andpotentially correlate with increased vessel wall monocyte recruitment.

MCP-1 is a potential player in negative cross talk between adiposetissue and skeletal muscle (Bianco J J, et al., Endocrinology, 2458(2006)). MCP-1 can significantly reduce insulin-stimulated glucoseuptake, and is a prominent inducer of insulin resistance in humanskeletal muscle cell. Adipose tissue is a major secretory and endocrineactive organ producing bioactive proteins regulating energy metabolismand insulin sensitivity.

CCR2 modulates inflammatory and metabolic effects of high-fat feeding(Weisberg S P, et al., J. Clin. Invest., 115 (2006)). Genetic deficiencyin CCR2 reduced food intake and attenuated the development of obesity inmice fed a high fat diet. In obese mice matched for adiposity, CCR2deficiency reduced macrophage content and inflammatory profile ofadipose tissue, increased adiponectin expression, and improved glucosehomeostatis and insulin sensitivity. In lean animals, no effect of CCR2genotype on metabolic trait was found. In high-fat diet mice, CCR2genotype modulated feeding, the development of obesity and adiposetissue inflammation. Once established, short term antagonism was shownto attenuate macrophage accumulation in adipose tissue and insulinresistance.

Chemokine and chemokine receptors are the key regulators of immune celltrafficking. MCP-1 is a potent chemoattractant of monocytes and T cells;its expression is induced under inflammatory conditions includingproinflammatory cytokine stimulations and hypoxia. The interactionbetween MCP-1 and CCR2 mediates migration of monocytes, macrophage aswell as activated T cells and play a key role in the pathogenesis ofmany inflammatory diseases. Inhibition of CCR2 functions using smallmolecule antagonists described in this invention represents a newapproach for the treatments of inflammatory disorders.

Psoriasis is a chronic inflammatory disease characterized byhyperproliferation of keratinocytes and pronounced leukocyteinfiltration. It is known that keratinocytes from psoriasis lesionexpress abundant CCR2 ligand MCP-1, particularly when stimulated byproinflammatory cytokines such as TNF-α (Vestergaard et al., Acta. Derm.Venereol., 84(5):353-8 (2004); Gillitzer et al., J. Invest. Dermatol.,101(2):127-31 (1993); Deleuran et al., J. Dermatol. Sci., 13(3):228-36(1996)). Since MCP-1 can attract migration of both macrophages anddendritic cells expressing CCR2 to the skin, this receptor and ligandpair is believed to be important in regulating the interaction betweenproliferating keratinocytes and dermal macrophage during the developmentof psoriasis. A small molecule antagonist may thus be useful in thetreatment of psoriasis.

In addition to inflammatory diseases, chemokines and chemokine receptorshave also been implicated in cancers (Broek et al., Br. J. Cancer,88(6):855-62 (2003)). Tumor cells stimulate the formation of stroma thatsecretes various mediators pivotal for tumor growth, including growthfactors, cytokines, and proteases. It is known that the level of MCP-1is associated significantly with tumor-associated macrophageaccumulation, and prognostic analysis reveals that high expression ofMOP-1 is a significant indicator of early relapse in breast cancer (Uenoet al., Clin. Cancer Res., 6(8):3282-9 (2001)). A small moleculeantagonist of a chemokine may thus be able to reduce the release ofgrowth-stimulating cytokines by blocking accumulation of macrophages atsites of tumor formation.

T lymphocyte (T cell) infiltration into the small intestine and colonhas been linked to the pathogenesis of Coeliac diseases, food allergies,rheumatoid arthritis, human inflammatory bowel diseases (IBD) whichinclude Crohn's disease and ulcerative colitis. Blocking trafficking ofrelevant T cell populations to the intestine can lead to an effectiveapproach to treat human IBD. More recently, chemokine receptor 9 (CCR9)has been noted to be expressed on gut-homing T cells in peripheralblood, elevated in patients with small bowel inflammation such asCrohn's disease and celiac disease. The only CCR9 ligand identified todate, TECK (thymus-expressed chemokine) is expressed in the smallintestine and the ligand receptor pair is now thought to play a pivotalrole in the development of IBD. In particular, this pair mediates themigration of disease causing T cells to the intestine. See for example,Zaballos et al., J. Immunol., 162(10):5671 5675 (1999); Kunkel et al.,J. Exp. Med., 192(5):761-768 (2000); Papadakis et al., J. Immunol.,165(9):5069-5076 (2000); Papadakis et al., Gastroenterology,121(2):246-254 (2001); Campbell et al., J. Exp. Med., 195(1):135-141(2002); Wurbel et al., Blood, 98(9):2626-2632 (2001); and Uehara et al.,J. Immunol., 168(6):2811-2819 (2002). Rivera-Nieves, et al.,Gastroenterology, 2006 November; 131(5):1518-29; and Kontoyiannis etal., J. Exp. Med., Vol. 196, Number 12, Dec. 16, 2002. In addition CCR9bearing lymphocytes have been show to mediate the pathology offilariasis (lymphatic filarial disease) and inhibition of CCR9 has beencorrelated with reduction of the pathology associated with suchconditions. See for example Babu et al., Journal of Infectious Diseases,191: 1018-26, 2005.

PCT Published Application WO 2003/099773 (Millennium Pharmaceuticals,Inc.) discloses compounds which can bind to CCR9 receptors of theformula

PCT Published Application WO 2005/004810 (Merck & Co., Inc.) disclosesbrandykinin B1 antagonists or inverse agonists of the formula

US Published Patent Application 2007/0037794 A1 (ChemoCentryx, Inc.)discloses CCR2 modulators of the formula

BRIEF SUMMARY

The present invention is directed to compounds and pharmaceuticallyacceptable salts thereof, compositions, and methods useful in modulatingchemokine activity. The compounds and salts thereof, compositions, andmethods described herein are useful in treating or preventingchemokine-mediated conditions or diseases, including certaininflammatory and immunoregulatory disorders and diseases.

The compounds of the present invention have been shown to modulate oneor more of CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR3,CXCR4, CXCR5, and CX3CR1. In particular, various compounds of thepresent invention modulate CCR2 and CCR9 as shown in the examples.

In one embodiment, the present compound may be represented by formula(I) or salts thereof:

where Ar, R¹, R², Y¹, Y², Y³, and Y⁴ are as defined below.

In another aspect, the present invention provides compositions useful inmodulating chemokine activity. In one embodiment, a compositionaccording to the present invention comprises a compound according to theinvention and a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofmodulating chemokine function in a cell, comprising contacting the cellwith a therapeutically effective amount of a compound or compositionaccording to the invention.

In still another aspect, the present invention provides a method formodulating chemokine function, comprising contacting a chemokinereceptor with a therapeutically effective amount of a compound orcomposition according to the invention.

In still another aspect, the present invention provides a method fortreating a chemokine-mediated condition or disease, comprisingadministering to a subject a safe and effective amount of a compound orcomposition according to the invention.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated withchemokine signaling activity.

DETAILED DESCRIPTION

General

The present invention is directed to compounds and salts thereof,compositions and methods useful in the modulation of chemokine receptorfunction, particularly CCR2 or CCR9 function. Modulation of chemokinereceptor activity, as used herein in its various forms, is intended toencompass antagonism, agonism, partial antagonism, inverse agonismand/or partial agonism of the activity associated with a particularchemokine receptor, preferably the CCR2 or CCR9 receptor. Accordingly,the compounds of the present invention are compounds which modulate atleast one function or characteristic of mammalian CCR2 or CCR9, forexample, a human CCR2 or CCR9 protein. The ability of a compound tomodulate the function of CCR2 or CCR9, can be demonstrated in a bindingassay (e.g., ligand binding or agonist binding), a migration assay, asignaling assay (e.g., activation of a mammalian G protein, induction ofrapid and transient increase in the concentration of cytosolic freecalcium), and/or cellular response assay (e.g., stimulation ofchemotaxis, exocytosis or inflammatory mediator release by leukocytes).

Abbreviations and Definitions

When describing the compounds, compositions, methods and processes ofthis invention, the following terms have the following meanings, unlessotherwise indicated.

“Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.Alkyl groups can be substituted or unsubstituted, unless otherwiseindicated. Examples of substituted alkyl include haloalkyl, thioalkyl,aminoalkyl, and the like.

“Alkoxy” refers to —O-alkyl. Examples of an alkoxy group includemethoxy, ethoxy, n-propoxy etc.

“Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl,cyclopentenyl and the like. Alkenyl groups can be substituted orunsubstituted, unless otherwise indicated.

“Alkynyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkynyl groups with2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. Alkynyl groups canbe substituted or unsubstituted, unless otherwise indicated.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having asingle ring (monocyclic) or multiple rings (bicyclic), which can befused together or linked covalently. Aryl groups with 6-10 carbon atomsare preferred, where this number of carbon atoms can be designated byC₆₋₁₀, for example. Examples of aryl groups include phenyl andnaphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groupscan be substituted or unsubstituted, unless otherwise indicated.

“Halo” or “halogen”, by itself or as part of a substituent refers to achlorine, bromine, iodine, or fluorine atom.

“Haloalkyl”, as a substituted alkyl group, refers to a monohaloalkyl orpolyhaloalkyl group, most typically substituted with from 1-3 halogenatoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyland the like.

“Heterocyclyl” refers to a saturated or unsaturated non-aromatic ringcontaining at least one heteroatom (typically 1 to 5 heteroatoms)selected from nitrogen, oxygen or sulfur. The heterocyclyl ring may bemonocyclic or bicyclic. Preferably, these groups contain 0-5 nitrogenatoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, thesegroups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Examples of heterocycle groups include pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidineand the like. Preferred heterocyclic groups are monocyclic, though theymay be fused or linked covalently to an aryl or heteroaryl ring system.

In one preferred embodiment, heterocyclic groups may be represented byformula (AA) below:

where formula (AA) is attached via a free valence on either Ma or M²; M¹represents O, NR^(e), or S(O)_(l); M² represents CR^(f)R^(g), O,S(O)_(l), or NR^(e); l is 0, 1 or 2; j is 1, 2 or 3 and k is 1, 2 or 3,with the proviso that j+k is 3, 4, or 5; and R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are independently selected from the groupconsisting of hydrogen, halogen, unsubstituted or substituted C₁₋₈alkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted C₂₋₈ alkynyl, —COR^(h), —CO₂R^(h), —CONR^(h)R^(i),—NR^(h)COR^(i), —SO₂R^(h), —SO₂NR^(h)R^(i), —NSO₂R^(h)R^(i)—NR^(h)R^(i), —OR^(h), -Q¹COR^(h), -Q¹CO₂R^(h), -Q¹CONR^(h)R^(i),-Q¹NR^(h)COR^(i), -Q¹SO₂R²⁸, -Q¹SO₂NR^(h)R^(i), -Q¹NSO₂R^(h)R^(i),-Q¹NR^(h)R^(i), -Q¹OR^(h), wherein Q¹ is a member selected from thegroup consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene,and R^(h) and R^(i) are independently selected from the group consistingof hydrogen and C₁₋₈ alkyl, and wherein the aliphatic portions of eachof the R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h) and R^(i)substituents are optionally substituted with from one to three membersselected from the group consisting of halogen, —OH, —OR^(n),—OC(O)NHR^(n), —OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(n), —S(O)₂R^(n),—SO₂NH₂, —S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n),—NR^(n)S(O)₂R^(o), —C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n),—NHC(O)R^(o), —NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂,—NR^(n)C(O)NHR^(o), —NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p),—NHC(O)NR^(n)R^(o), —CO₂H, —CO₂R^(n), —NHCO₂R^(n), —NR^(n)CO₂R^(o), —CN,—NO₂, —NH₂, —NHR^(n), —NR^(n)R^(o), —NR^(n)S(O)NH₂ and—NR^(n)S(O)₂NHR^(o), wherein R^(n), R^(o) and R^(p) are independently anunsubstituted C₁₋₈ alkyl. Additionally, any two of R^(a), R^(b), R^(c),R^(d), R^(e), R^(f) and R^(g) may be combined to form a bridged orspirocyclic ring system.

In one preferred embodiment, the number of R^(a)+R^(b)+R^(c)+R^(d)groups that are other than hydrogen is 0, 1 or 2. In a more preferredembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), and R^(g) areindependently selected from the group consisting of hydrogen, halogen,unsubstituted or substituted C₁₋₈ alkyl, —COR^(h), —CO₂R^(h),—CONR^(h)R^(h), —NR^(h)COR^(h), —SO₂R^(h), —SO₂NR^(h)R^(i),—NSO₂R^(h)R^(i), —NR^(h)R^(i), and —OR^(h), wherein R^(h) and R^(i) areindependently selected from the group consisting of hydrogen andunsubstituted C₁₋₈ alkyl and wherein the aliphatic portions of each ofthe R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) substituents areoptionally substituted with from one to three members selected from thegroup consisting of halogen, —OH, —OR^(n), —OC(O)NHR^(n),—OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(o), —S(O)₂R^(n), —SO₂NH₂,—S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n), —NR^(n)S(O)₂R^(o),—C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n), —NHC(O)R^(n),—NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂, —NR^(n)C(O)NHR^(o),—NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p), —NHC(O)NR^(n)R^(o), —CO₂H,—CO₂R^(n), —NHCO₂R^(n), —NR^(n)CO₂R^(o), —CN, —NO₂, —NH₂, —NHR^(n),—NR^(n)R^(o), —NR^(n)S(O)NH₂ and —NR^(n)S(O)₂NHR^(o), wherein R^(n),R^(o) and R^(p) are independently an unsubstituted C₁₋₈ alkyl.

In a more preferred embodiment, R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), and R^(g) are independently hydrogen or C₁₋₄ alkyl. In anotherpreferred embodiment, at least three of R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are hydrogen.

“Heteroaryl” refers to an aromatic group containing at least oneheteroatom, where the heteroaryl group may be monocyclic or bicyclic.Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,azaindolyl, azaindazolyl, quinolyl, isoquinolyl, isothiazolyl,pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl,furyl or thienyl. Preferred heteroaryl groups are those having at leastone aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl,quinolyl, isoquinolyl and the like. Preferred 6-ring heteroaryl systemsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and thelike. Preferred 5-ring heteroaryl systems include isothiazolyl,pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.

Heterocyclyl and heteroaryl can be attached at any available ring carbonor heteroatom. Each heterocyclyl and heteroaryl may have one or morerings. When multiple rings are present, they can be fused together orlinked covalently. Each heterocyclyl and heteroaryl must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Heterocyclyl and heteroaryl groups can be substituted orunsubstituted, unless otherwise indicated. For substituted groups, thesubstitution may be on a carbon or heteroatom. For example, when thesubstitution is oxo (═O or —O⁻), the resulting group may have either acarbonyl (—C(O)—) or a N-oxide (—N⁺—O⁻).

Suitable substituents for substituted alkyl, substituted alkenyl, andsubstituted alkynyl include halogen, —CN, —CO₂R′, —C(O)R′, —C(O)NR′R″,oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO₂, —NR′C(O)R′,—NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R′″,—NR′″S(O)NR′R″, —NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl. The numberof possible substituents range from zero to (2m′+1), where m′ is thetotal number of carbon atoms in such radical.

Suitable substituents for substituted aryl, substituted heteroaryl andsubstituted heterocyclyl include halogen, —CN, —CO₂R′, —C(O)R′,—C(O)NR′R″, oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO₂,—NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R″,—NR′″S(O)NR′R″, —NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10 membered heterocyclyl. The numberof possible substituents range from zero to the total number of openvalences on the aromatic ring system.

As used above, R′, R″ and R′″ each independently refer to a variety ofgroups including hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and4-morpholinyl). Furthermore, R′ and R″, R″ and R′″, or R′ and R′″ maytogether with the atom(s) to which they are attached, form a substitutedor unsubstituted 5-, 6- or 7-membered ring.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NR″″—, —O—,—CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A′—(CH₂)_(r)—B′—, wherein A′ and B′ are independently —CH₂—,—O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR″″— or a single bond, and ris an integer of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.R″″ in is selected from hydrogen or unsubstituted C₁₋₈ alkyl.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

“Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

“Salt thereof” refers to a compound formed when the hydrogen of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Preferably, the salt is a pharmaceutically-acceptable salt,although this is not required for salts of intermediate compounds whichare not intended for administration to a patient.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs may be prepared by modifying functional groups present in thecompounds in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compounds. Prodrugsinclude compounds wherein hydroxyl, amino, sulfhydryl, or carboxylgroups are bonded to any group that, when administered to a mammaliansubject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxylgroup respectively. Examples of prodrugs include, but are not limitedto, acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention. Preparation,selection, and use of prodrugs is discussed in T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. SymposiumSeries; “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985; and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, each of which arehereby incorporated by reference in their entirety.

The compounds of the invention may be present in the form ofpharmaceutically acceptable metabolites thereof. The term “metabolite”means a pharmaceutically acceptable form of a metabolic derivative of acompound of the invention (or a salt thereof). In some aspects, themetabolite may be a functional derivative of a compound that is readilyconvertible in vivo into an active compound. In other aspects, themetabolite may be an active compound.

“Therapeutically effective amount” refers to an amount sufficient toeffect treatment when administered to a patient in need of treatment.

“Treating” or “treatment” as used herein refers to the treating ortreatment of a disease or medical condition (such as a viral, bacterialor fungal infection or other infectious diseases, as well as autoimmuneor inflammatory conditions) in a patient, such as a mammal (particularlya human or a companion animal) which includes ameliorating the diseaseor medical condition, i.e., eliminating or causing regression of thedisease or medical condition in a patient; suppressing the disease ormedical condition, i.e., slowing or arresting the development of thedisease or medical condition in a patient; or alleviating the symptomsof the disease or medical condition in a patient.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, bothsolvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present invention and are intended to bewithin the scope of the present invention.

It will be apparent to one skilled in the art that certain compounds ofthe present invention may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the invention. Certaincompounds of the present invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention. The compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(3H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The compounds of the present invention may include a detectable label. Adetectable label is a group that is detectable at low concentrations,usually less than micromolar, possibly less than nanomolar, and that canbe readily distinguished from other molecules, due to differences in amolecular property (e.g. molecular weight, mass to charge ratio,radioactivity, redox potential, luminescence, fluorescence,electromagnetic properties, binding properties, and the like).Detectable labels may be detected by spectroscopic, photochemical,biochemical, immunochemical, electrical, magnetic, electromagnetic,optical or chemical means and the like.

A wide variety of detectable labels are within the scope of the presentinvention, including hapten labels (e.g. biotin, or labels used inconjunction with detectable antibodies such as horse radish peroxidaseantibodies); mass tag labels (e.g. stable isotope labels); radioisotopiclabels (including H³, I¹²⁵, S³⁵, C¹⁴, or P³²); metal chelate labels;luminescent labels including fluorescent labels (such as fluorescein,isothiocyanate, Texas red, rhodamine, green fluorescent protein, and thelike), phosphorescent labels, and chemiluminescent labels, typicallyhaving quantum yield greater than 0.1; electroactive and electrontransfer labels; enzyme modulator labels including coenzymes,organometallic catalysts horse radish peroxidase, alkaline phosphataseand others commonly used in an ELISA; photosensitizer labels; magneticbead labels including Dynabeads; colorimetric labels such as colloidalgold, silver, selenium, or other metals and metal sol labels (see U.S.Pat. No. 5,120,643, which is herein incorporated by reference in itsentirety for all purposes), or colored glass or plastic (e.g.,polystyrene, polypropylene, latex, etc.) bead labels; and carbon blacklabels. Patents teaching the use of such detectable labels include U.S.Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437;4,275,149; 4,366,241; 6,312,914; 5,990,479; 6,207,392; 6,423,551;6,251,303; 6,306,610; 6,322,901; 6,319,426; 6,326,144; and 6,444,143,which are herein incorporated by reference in their entirety for allpurposes.

Detectable labels are commercially available or may be prepared as knownto one skilled in the art. Detectable labels may be covalently attachedto the compounds using a reactive functional group, which can be locatedat any appropriate position. Methods for attaching a detectable labelare known to one skilled in the art. When the reactive group is attachedto an alkyl, or substituted alkyl chain tethered to an aryl nucleus, thereactive group may be located at a terminal position of an alkyl chain.

Compounds

In one embodiment, the compounds of the present invention arerepresented by formula (I), or salts thereof:

Ar is selected from the group consisting of substituted or unsubstitutedC₆₋₁₀ aryl and substituted or unsubstituted 5- to 10-memberedheteroaryl.

Y¹ is selected from the group consisting of —CR^(3a)—, —N—, and—N⁺(O)⁻—;

Y² is selected from the group consisting of —CR^(3b)—, —N—, and—N⁺(O)⁻—;

Y³ is selected from the group consisting of —CR^(3c)—, —N—, and—N⁺(O)⁻—;

Y⁴ is selected from the group consisting of —CR^(3d)—, —N—, and—N⁺(O)⁻—;

wherein at least one of Y¹, Y², Y³, or Y⁴ is —N—.

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently selected fromthe group consisting of hydrogen, halogen, —CN, —C(O)R⁴, —CO₂R⁴,—C(O)NR⁴R⁵, —OR⁴, —OC(O)R⁴, —OC(O)NR⁴R⁵, —SR⁴, —S(O)R⁴, —S(O)₂R⁴,—S(O)₂NR⁴R⁵, —NO₂, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)OR⁵, —NR⁴S(O)₂R⁵,—NR⁴C(O)NR⁵R⁶, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl;

R⁴, R⁵, and R⁶ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl;

R⁴ and R⁵, R⁵ and R⁶ or R⁴ and R⁶ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring;

R¹ is selected from the group consisting of hydrogen, —C(O)R⁷, —CO₂R⁷,—C(O)NR⁷R⁸, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂NR⁷R⁸, substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl;

R² is selected from the group consisting of hydrogen, halogen, —CN,—C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷, —OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷,—S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)OR⁸,—NR⁷S(O)₂R⁸, —NR⁷C(O)NR⁸R⁹, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl;

R⁷, R⁸, and R⁹ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted O₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl;

R⁷ and R⁸, R⁸ and R⁹ or R⁷ and R⁹ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring; and

where R¹ and R² may, together with the atoms to which they are attached,form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

with the proviso thatN-(1,1-dimethylethyl)-3-[2-[[[3-(5,5-dimethyl-3-octadecyl-2-thiazolidinyl)-4-hydroxyphenyl]sulfonyl]amino]-4-hydroxy-6-methylphenyl]-7-[[4-[ethyl]2-[(methylsulfonyl)amino]ethyl]amino]phenyl]imino]-7H-pyrazolo[5,1-c]-1,2,4-triazole-6-carboxamideis excluded from the scope of formula (I).

In a further embodiment, the compounds are represented by formula (II),or salts thereof:

Formula II is an example of Formula I.

Ar, R¹ and R² are as defined above.

Y⁵, Y⁶ and Y⁷ are each independently selected from the group consistingof hydrogen, halogen, —CN, —C(O)R¹⁵, —CO₂R¹⁵, —C(O)NR¹⁵R¹⁶, —OR¹⁵,—OC(O)R¹⁵, —OC(O)NR¹⁵R¹⁶, —SR¹⁵, —S(O)R¹⁵, —S(O)₂R¹⁵, —S(O)₂NR¹⁵R¹⁶,—NO₂, —NR¹⁵R¹⁶, —NR¹⁵C(O)R¹⁶, —NR¹⁵C(O)OR¹⁶, —NR¹⁵S(O)₂R¹⁶,—NR¹⁵C(O)NR¹⁶R¹⁷, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ alkyl, and substituted or unsubstituted 5- to10-membered heteroaryl;

R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R¹⁵ and R¹⁶, R¹⁶ and R¹⁷ or R¹⁵ and R¹⁷ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

In another embodiment, the compounds are represented by formula (III),or salts thereof:

Formula IV is an example of Formula I.

R¹, R², Y⁵, Y⁶ and Y⁷ are each as defined above.

X¹, X², X³, X⁴, and X⁵ are each independently selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹,—OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NO₂, —NR¹⁸C(O)R¹⁹, —NR¹⁸C(O)NR¹⁹R²⁰,—NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸, —S(O)₂NR¹⁸,—S(O)₂NR¹⁸R¹⁹, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R¹⁸, R¹⁹ and R²⁰ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R¹⁸ and R¹⁹, R¹⁹ and R²⁰ or R¹⁸ and R²⁰ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

In one embodiment, the compounds of the present invention arerepresented by formula (IV), or salts thereof:

wherein X¹ and X² are each independently from the group consisting ofhalogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, —CO₂R¹⁸, —OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹,—NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —NO₂, and —SR¹⁸;

Y⁶ is selected from the group consisting of halogen, —CN, —OR¹⁸, andsubstituted or unsubstituted C₁₋₈ alkyl;

R¹ is selected from the group consisting of hydrogen, —C(O)R⁷, —CO₂R⁷,—C(O)NR⁷R⁸, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂NR⁷R⁸, substituted or unsubstitutedC₁₋₈ alkyl, C₁₋₈ substituted or unsubstituted cycloalkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl;

R² is selected from the group consisting of hydrogen, halogen, —CN,—C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷, —OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷,—S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)OR⁸,—NR⁷S(O)₂R⁸, —NR⁷C(O)NR⁸R⁹, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl;

where R¹ and R² may, together with the atoms to which they are attached,form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

R⁷, R⁸, and R⁹ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; and

R⁷ and R⁸, R⁸ and R⁹ or R⁷ and R⁹ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

R¹⁸, R¹⁹ and R²⁰ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R¹⁸ and R¹⁹, R¹⁹ and R²⁰ or R^(1B) and R²⁰ may, together with the atomsto which they are attached, form a substituted or unsubstituted 5-, 6-,or 7-membered ring;

In another embodiment, the compounds of the present invention arerepresented by formula (V), or salts thereof:

wherein X¹, X², Y⁶, and R² are as defined above for formula (IV).

In another embodiment, the compounds of the present invention arerepresented by formula (VI), or salts thereof:

wherein X¹, X², Y⁶, and R² are as defined above for formula (IV).

In another embodiment, the compounds of the present invention arerepresented by formula (VII), or salts thereof:

wherein X¹, X², Y⁶, and R² are as defined above for formula (IV) and Zis 0, 1, 2, 3, 4, or 5 substituents selected from the group consistingof halogen, substituted or unsubstituted C₁₋₈ alkyl, and substituted orunsubstituted C₁₋₈ alkoxy.

In another embodiment, the compounds of the present invention arerepresented by formula (VIII), or salts thereof:

wherein Y⁶, R¹ and R² are as defined above for formula (I).

In another embodiment, the compounds of the present invention arerepresented by formula (IX), or salts thereof:

where R² is as defined in formula (IV) and R³ and R⁴ are eachindependently hydrogen, unsubstituted or substituted C₁₋₈ alkyl, or R³and R⁴ together with the carbon which they substitute form a 3-10membered carboxylic, 4-10 membered heterocyclic or 5-10 memberedheteroaryl ring.

Formulae II, III, IV, V, VI, VII, VIII, IX, and XI are examples ofFormula I.

Compounds that Modulate CCR2 or CCR9 Activity

The present invention provides compounds that modulate at least one ofCCR2 or CCR9 activity. Chemokine receptors are integral membraneproteins which interact with an extracellular ligand, such as achemokine, and mediate a cellular response to the ligand, e.g.,chemotaxis, increased intracellular calcium ion concentration, etc.Therefore, modulation of a chemokine receptor function, e.g.,interference with a chemokine receptor ligand interaction, will modulatea chemokine receptor mediated response, and treat or prevent a chemokinereceptor mediated condition or disease. Modulation of a chemokinereceptor function includes both inducement and inhibition of thefunction. The type of modulation accomplished will depend on thecharacteristics of the compound, i.e., antagonist or full, partial orinverse agonist.

Without intending to be bound by any particular theory, it is believedthat the compounds provided herein interfere with the interactionbetween a chemokine receptor and one or more cognate ligands. Inparticular, it is believed that the compounds interfere with theinteraction between CCR2 and a CCR2 ligand, such as MCP-1. Compoundscontemplated by the invention include, but are not limited to, theexemplary compounds provided herein and salts thereof.

For example, compounds of this invention act as potent CCR2 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR2.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR2-mediated diseases, andas controls in assays for the identification of competitive CCR2antagonists.

The compounds of the invention are thought to interfere withinappropriate T-cell trafficking by specifically modulating orinhibiting a chemokine receptor function. Without intending to be boundby any particular theory, it is believed that the compounds providedherein interfere with the interaction between a chemokine receptor andone or more cognate ligands. In particular, it is believed that thecompounds interfere with the interaction between CCR9 and a CCR9 ligand,such as TECK. Compounds contemplated by the invention include, but arenot limited to, the exemplary compounds provided herein and saltsthereof.

For example, compounds of this invention act as potent CCR9 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR9.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR9-mediated diseases, andas controls in assays for the identification of competitive CCR9antagonists.

Known Compound

The compound shown below:

also referred to asN-(1,1-dimethylethyl)-3-[2-[[[3-(5,5-dimethyl-3-octadecyl-2-thiazolidinyl)-4-hydroxyphenyl]sulfonyl]amino]-4-hydroxy-6-methylphenyl]-7-[[4-[ethyl[2-[(methylsulfonyl)amino]ethyl]amino]phenyl]imino]-7H-pyrazolo[5,1-c]-1,2,4-triazole-6-carboxamide,is known, but not as a CCR9 or CCR2 antagonist.

PREFERRED EMBODIMENTS

In the following descriptions and embodiments, references to specificsubstituents only correspond to formula numbers in which those specificsubstituents are present or appear.

In one embodiment of formula I, Y⁴ is —N—.

Preferred Ar Groups

In one embodiment of any the formula I, Ar is selected from the groupconsisting of substituted or unsubstituted C₆₋₁₀ aryl and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of any the formula I, Ar is a C₆₋₁₀ aryl with at least2 substituents other than hydrogen.

In one embodiment of any the formula I, Ar is a substituted orunsubstituted bicyclic aryl or substituted or unsubstituted bicyclicheteroaryl.

In one embodiment of any the formula a, Ar is selected from the groupconsisting of:

In one embodiment of formulae (I or II), Ar is substituted phenyl.

Preferred X Groups

In one embodiment of formulae (III, IV, V, VI, VII, or XI), both X¹ andX² are selected from the group consisting of halogen, —CN, and —CF₃.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), one of X¹and X² is halogen and one of X¹ and X² is selected from the groupconsisting of halogen, —CN, and —CF₃.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ ischloro.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ ismethyl.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ isselected from the group consisting of substituted C₁₋₈ alkyl orunsubstituted C₂₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl, andsubstituted or unsubstituted C₂₋₈ alkynyl.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ is anunsubstituted C₂₋₈ alkyl.

In one embodiment of formulae (III, IV, V, VI, VII or XI), X¹ is otherthan methyl.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ ist-butyl.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ isisopropoxy.

In one embodiment of formulae (III, IV, V, VI, VII, or XII), X¹ ismorpholine.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X² is —CF₃.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X² ischloro.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X² isfluoro.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ is chloroand X² is —CF₃.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ is chloroand X² is chloro.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ is methyland X² is —CF₃.

In one embodiment of formulae (III, IV, V, VI, VII, or XI), X¹ ismorpholine and X² is fluoro.

Preferred Y Groups

In one embodiment of any of formulae (II and III) Y⁵, Y⁶, and Y⁷ areeach independently selected from the group consisting of hydrogen,fluorine, chlorine, and bromine, where one of Y⁵, Y⁶, and Y⁷ is otherthan hydrogen.

In another embodiment of any of formulae (II and III), at least one ofY⁵, Y⁶, and Y⁷ is other than hydrogen; preferably Y⁶ is halogen.

In another embodiment of any of formulae (II and III), at least one ofY⁵, Y⁶, and Y⁷ is other than hydrogen; preferably Y⁶ is halogen.

In another embodiment of any of formulae (II and III), Y⁵ and Y⁷ arehydrogen and Y⁶ is halogen.

In another embodiment of any of formulae (II and III), Y⁵ and Y⁷ arehydrogen and Y⁶ is chloro.

In one embodiment of any of formulae (II and III), Y⁵ and Y⁷ arehydrogen, and Y⁶ is —CH₃.

In one embodiment of any of formulae (II, III, IV, V, VI, VII, VIII, andXI), Y⁶ is selected from the group consisting of halogen, —CN, —OR¹⁵,and substituted or unsubstituted C₁₋₈ alkyl.

In one embodiment of any of (II, III, IV, V, VI, VII, VIII, and XI), Y⁶is selected from the group consisting of —Cl, —Br, —F, —OCH₃, —CH₃,—CF₃, and —CN

In one embodiment of any of formulae (II, III, IV, V, VI, VII, VIII, andXI), Y⁶ is selected from the group consisting of —Cl, —Br, —F, and—OCH₃.

In one embodiment of any of formulae (II, III, IV, V, VI, VII, VIII, andXI), Y⁶ is halogen.

In one embodiment of any of formulae (II, III, IV, V, VI, VII, VIII, andXI), Y⁶ is bromine.

In one embodiment of any of formulae (II, III, IV, V, VI, VII, VIII, andXI), Y⁶ is chloro.

Preferred R¹ and R² Groups

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is otherthan hydrogen.

In one embodiment of formulae (I, II, III, IV, or VII), R¹ is selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 5- to 6-memberedheterocyclyl, substituted or unsubstituted phenyl, and substituted orunsubstituted 5- to 6-membered heteroaryl.

In one embodiment of formulae (I, II, III, IV, or VII), R¹ issubstituted or unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ issubstituted or unsubstituted phenyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is methyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is ethyl.

In one embodiment of formulae (I, II, III, IV, or VII), R¹ is isopropyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ issubstituted or unsubstituted 5- to 6-membered heteroaryl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ issubstituted or unsubstituted 5- to 6-membered heterocyclyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is methyl,ethyl or isopropyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ is selectedfrom the group consisting of unsubstituted or substituted phenyl,unsubstituted or substituted pyridyl, and unsubstituted or substitutedpyrazolyl.

In one embodiment of formulae (I, II, III, IV, or VIII) R¹ issubstituted or unsubstituted oxazole.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ issubstituted or unsubstituted pyrrolidinyl.

In one embodiment of formulae (I, II, III, IV, or VIII), R¹ issubstituted or unsubstituted piperidinyl.

In one embodiment of formulae (I, II, III IV, or VIII), R¹ is one memberof the group consisting of:

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is other than hydrogen.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is hydrogen.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is methyl

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI, R² is ethyl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is isopropyl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is selected from the group consisting of halogen, —CN, —C(O)R⁷,—CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷, —OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷,—S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)OR⁸,—NR⁷S(O)₂R⁸, and —NR⁷C(O)NR⁸R⁹.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is selected from the group consisting of substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is selected from the group consisting of substituted orunsubstituted 5- to 6-membered heterocyclyl, substituted orunsubstituted phenyl, and substituted or unsubstituted 5- to 6-memberedheteroaryl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is substituted or unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is substituted or unsubstituted 5- to 6-membered heterocyclyl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is substituted or unsubstituted 5-to-6-membered heteroaryl.

In one embodiment of formulae (I, II, III, IV, V, VI, VII, VIII, IX, orXI), R² is methyl.

Preferred R³ and R⁴ Groups

In one embodiment of formula (IX), R³ and R⁴ are each hydrogen.

In one embodiment of formula (IX), one of R³ and R⁴ is hydrogen and theother is unsubstituted or substituted C₁₋₈ alkyl.

In one embodiment of formula (IX), both of R³ and R⁴ are unsubstitutedor substituted C₁₋₈ alkyl.

In one embodiment of formula (IX), R³ and R⁴ together with the carbonwhich they substitute form a 3-10 membered carboxylic ring.

In one embodiment of formula (IX), R³ and R⁴ together with the carbonwhich they substitute form a 4-10 membered heterocyclic ring.

In one embodiment of formula (IX), R³ and R⁴ together with the carbonwhich they substitute form a 5-10 membered heteroaryl ring.

Exemplary Compounds

The following compounds are within the scope of the formula (I):

-   tert-butyl    3-(3-(3-(4-tert-butylphenylsulfonamido)-5-methylpyridin-2-yl)-4H-1,2,4-triazol-4-yl)pyrrolidine-1-carboxylate;-   ethyl    5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;-   5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;-   5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N-methyl-4H-1,2,4-triazole-3-carboxamide;-   N-(5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)acetamide;-   (S)-4-tert-butyl-N-(5-chloro-2-(4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   (S)-4-tert-butyl-N-(5-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   (S)-4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-(2-hydroxypropan-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-(isoxazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-methyl-2-(4-(1-methylpyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-methyl-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   ethyl    5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxylate;-   ethyl    5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;-   5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-phenyl-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(3,4-dichlorophenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)-phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-isopropyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   5-(5-chloro-3-(4-methyl-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;-   (S)-4-chloro-N-(5-chloro-2-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   3,4-dichloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-((3S,4S)-4-methoxypyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(1-(dimethylamino)propan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(3-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(4-hydroxybutan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(4-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-(4-(5-fluoro-2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(morpholine-4-carbonyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(pyrrolidine-1-carbonyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-(5-chloro-2-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-o-tolyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-((dimethylamino)methyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-(methoxymethyl)-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-cyclopropyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-(5-chloro-2-(5-isopropyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-bromopyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;-   N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-methylpyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;-   N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(5-tert-butyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(5-bromo-4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;-   N-(2-(5-bromo-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-(2-(5-bromo-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;    and-   N-(5-bromo-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide.

Compositions that Modulate Chemokine Activity

In another aspect, the present invention provides compositions thatmodulate chemokine activity, specifically CCR2 activity or CCR9activity. Generally, the compositions for modulating chemokine receptoractivity in humans and animals will comprise a pharmaceuticallyacceptable excipient or diluent and a compound having the formulaprovided above as formula (I).

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. Pat. No.6,451,339, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents such as cellulose, silicon dioxide, aluminum oxide, calciumcarbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, corn starch, or alginic acid; binding agents, forexample PVP, cellulose, PEG, starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated enterically or otherwiseby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil in water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative. and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, axed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols. Additionally, the compounds can be administered via oculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds can be accomplished by means ofiontophoretic patches and the like.

For topical use, creams, ointments, jellies, solutions or suspensionscontaining the compounds of the present invention are employed. As usedherein, topical application is also meant to include the use of mouthwashes and gargles.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds as noted herein,such as those applied in the treatment of the above mentionedpathological conditions.

In one embodiment, the present invention provides a compositionconsisting of a pharmaceutically acceptable carrier and a compound ofthe invention.

Methods of Treatment

Depending on the disease to be treated and the subject's condition, thecompounds and compositions of the present invention may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each rouse of administration. The present invention alsocontemplates administration of the compounds and compositions of thepresent invention in a depot formulation.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the hostundergoing therapy.

In still other embodiments, the present methods are directed to thetreatment of allergic diseases, wherein a compound or composition of theinvention is administered either alone or in combination with a secondtherapeutic agent, wherein said second therapeutic agent is anantihistamine, When used in combination, the practitioner can administera combination of the compound or composition of the present inventionand a second therapeutic agent. Also, the compound or composition andthe second therapeutic agent can be administered sequentially, in anyorder.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

In treating, preventing, ameliorating, controlling or reducing the riskof inflammation, the compounds of the present invention may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonists a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, biological TNFsequestrants, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like.

Similarly, the compounds of the present invention may be administeredwith a pain reliever; a potentiator such as caffeine, an H2-antagonist,simethicone, aluminum or magnesium hydroxide; a decongestant such aspseudophedrine; an antitussive such as codeine; a diuretic; a sedatingor non-sedating antihistamine; a very late antigen (VLA-4) antagonist;an immunosuppressant such as cyclosporin, tacrolimus, rapamycin, EDGreceptor agonists, or other FK-506 type immunosuppressants; a steroid; anon-steroidal anti-asthmatic agent such as a β2-agonist, leukotrieneantagonist, or leukotriene biosynthesis inhibitor; an inhibitor ofphosphodiesterase type IV (PDE-IV); a cholesterol lowering agent such asa HMG-CoA reductase inhibitor, sequestrant, or cholesterol absorptioninhibitor; and an anti-diabetic agent such as insulin, α-glucosidaseinhibitors or glitazones.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Methods of Treating or Preventing CCR2-Mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR2-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. For example, compounds for use in treatingor preventing a CCR2-mediated condition or disease may include compoundsof the formula (I) wherein Ar is selected from the group consisting of:

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

As used herein, the phrase “CCR2-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR2functional activity. Inappropriate CCR2 functional activity might ariseas the result of CCR2 expression in cells which normally do not expressCCR2, increased CCR2 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR2 expression.Inappropriate CCR2 functional activity might also arise as the result ofMCP-1 secretion by cells which normally do not secrete MCP-1, increasedMCP-1 expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased MCP-1 expression. A CCR2-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR2 functional activity. However, a CCR2-mediatedcondition or disease is one in which modulation of CCR2 results in someeffect on the underlying condition or disease (e.g. a CCR2 antagonistresults in some improvement in patient well being in at least somepatients). Furthermore, MCP-2, 3 and 4 are also CCR2 ligands.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta sale and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease isatherosclerosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta sate and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is restenosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is multiplesclerosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is selected fromthe group consisting of inflammatory bowel disease, renal fibrosis,rheumatoid arthritis, obesity and non-insulin-dependent diabetes.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is type 2diabetes.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is selected fromthe group consisting of chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis and idiopathic pneumonia syndrome.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the administering is oral, parenteral, rectal,transdermal, sublingual, nasal or topical

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the compound is administered in combination with ananti-inflammatory or analgesic agent.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where an anti-inflammatory or analgesic agent is alsoadministered.

In one embodiment, the present invention provides a method of modulatingCCR2 function in a cell, where the CCR2 function in the cell ismodulated by contacting the cell with a CCR2 modulating amount of thecompound of the present invention.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the disease is selected from the group consisting ofpulmonary fibrosis, transplantation rejection, graft-versus-host diseaseand cancer.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis wherein a compound or composition of theinvention is used alone or in combination with a second therapeuticagent such as a corticosteroid, a lubricant, a keratolytic agent, avitamin D₃ derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as aβ2-agonist and a corticosteroid.

Methods of Treating or Preventing CCR9-Mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR9-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. For example, compounds for use in treatingor preventing a CCR9-mediated condition or disease may include compoundsof the formula (I) wherein Ar is selected from the group consisting of:

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

As used herein, the phrase “CCR9-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR9functional activity. Inappropriate CCR9 functional activity might ariseas the result of CCR9 expression in cells which normally do not expressCCR9, increased CCR9 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR9 expression.Inappropriate CCR9 functional activity might also arise as the result ofTECK secretion by cells which normally do not secrete TECK, increasedTECK expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased TECK expression. A CCR9-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR9 functional activity. However, a CCR9-mediatedcondition or disease is one in which modulation of CCR9 results in someeffect on the underlying condition or disease (e.g., a CCR9 antagonistresults in some improvement in patient well being in at least somepatients).

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa cell, tissue, system, or animal, such as a human, that is being soughtby the researcher, veterinarian, medical doctor or other treatmentprovider.

Diseases and conditions associated with inflammation, immune disorders,infection and cancer can be treated or prevented with the presentcompounds, compositions, and methods. In one group of embodiments,diseases or conditions, including chronic diseases, of humans or otherspecies can be treated with inhibitors of CCR9 function. These diseasesor conditions include: (1) allergic diseases such as systemicanaphylaxis or hypersensitivity responses, drug allergies, insect stingallergies and food allergies, (2) inflammatory bowel diseases, such asCrohn's disease, ulcerative colitis, ileitis and enteritis, (3)vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria andpruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma,(8) asthma and respiratory allergic diseases such as allergic asthma,allergic rhinitis, hypersensitivity lung diseases and the like, (9)autoimmune diseases, such as fibromyalagia, scleroderma, ankylosingspondylitis, juvenile RA, Still's disease, polyarticular juvenile RA,pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis,multiple sclerosis, systemic lupus erythematosus, type I diabetes, typeII diabetes, glomerulonephritis, and the like, (10) graft rejection(including allograft rejection), (11) graft-v-host disease (includingboth acute and chronic), (12) other diseases in which undesiredinflammatory responses are to be inhibited, such as atherosclerosis,myositis, neurodegenerative diseases (e.g., Alzheimer's disease),encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,allergic conjunctivitis, otitis, chronic obstructive pulmonary disease,sinusitis, Behcet's syndrome and gout, (13) immune mediated foodallergies such as Coeliac (Celiac) disease (14) pulmonary fibrosis andother fibrotic diseases, and (15) irritable bowel syndrome.

In another group of embodiments, diseases or conditions can be treatedwith modulators and agonists of CCR9 function. Examples of diseases tobe treated by modulating CCR9 function include cancers, cardiovasculardiseases, diseases in which angiogenesis or neovascularization play arole (neoplastic diseases, retinopathy and macular degeneration),infectious diseases (viral infections, e.g., HIV infection, andbacterial infections) and immunosuppressive diseases such as organtransplant conditions and skin transplant conditions. The term “organtransplant conditions” is means to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel diseaseincluding Crohn's disease and Ulcerative Colitis, allergic diseases,psoriasis, atopic dermatitis and asthma, autoimmune disease such asrheumatoid arthritis and immune-mediated food allergies such as Coelaicdisease.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis where a compound or composition of the inventionis used alone or in combination with a second therapeutic agent such asa corticosteroid, a lubricant, a keratolytic agent, a vitamin D₃derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as aβ2-agonist and a corticosteroid.

Preparation of Modulators

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Additionally, those skilled in the art will recognize that the moleculesclaimed in this patent may be synthesized using a variety of standardorganic chemistry transformations.

Certain general reaction types employed widely to synthesize targetcompounds in this invention are summarized in the examples.Specifically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

While not intended to be exhaustive, representative synthetic organictransformations which can be used to prepare compounds of the inventionare included below.

These representative transformations include; standard functional groupmanipulations; reductions such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckwald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nucleophilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

In the descriptions of the syntheses that follow, some precursors wereobtained from commercial sources. These commercial sources includeAldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated,Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

Compounds of the invention, including those listed in the table ofactivities, can be made by the methods and approaches described in thefollowing experimental section, and by the use of standard organicchemistry transformations that are well known to those skilled in theart.

EXAMPLES

Exemplary compounds used in the method of the invention and inpharmaceutical compositions of the invention include but are not limitedto the compounds listed in Table 1. Pharmaceutically acceptable salts ofthe compounds listed in Table 1 are also useful in the method of theinvention and in pharmaceutical compositions of the invention. TABLE 1Exemplary compounds X¹ X² Y⁶ R¹ R² 1. t- H Cl —CH(CH₃)₂ —CH₃ bu- tyl 2.t- H Cl —CH(CH₃)₂ H bu- tyl 3. t- bu- tyl H Cl —CH(CH₃)₂

4. t- H Cl —CH₃ H bu- tyl 5. t- H Cl —CH₃ —CH(CH₃)₂ bu- tyl 6. t- H Cl—CH₂CH₃ —CH₂OCH₃ bu- tyl 7. t- bu- tyl H Cl —CH₃

8. t- bu- tyl H Cl —CH(CH₃)₂

9. t- bu- tyl H Cl

H 10. t- H Cl —CH₂CH₃ H bu- tyl 11. t- H Cl —CH₃ —CH₃ bu- tyl 12. t- bu-tyl H Cl —CH₃

13. t- bu- tyl H Cl —CH₃

14. t- H Cl —CH₃ —CH₂OCH₃ bu- tyl 15. t- bu- tyl H Cl

H 16. t- bu- tyl H Cl

H 17. t- H Cl —CH₂CH₃ —CH₃ bu- tyl 18. t- bu- tyl H Cl —CH(CH₃)₂

19. t- H Cl —CH(CH₃)₂ —CH₂OCH₃ bu- tyl 20. t- H Cl C₆H₅ H bu- tyl 21. t-bu- tyl H Cl

—CH₃ 22. t- bu- tyl H Cl —CH₃

23. t- bu- tyl H CH₃

H 24. t- bu- tyl H Cl

25. t- bu- tyl H Cl

26. t- bu- tyl H Cl

—CH₂OCH₃ 27. t- H Cl —CH(CH₃)₂ NH₂ bu- tyl 28. t- bu- tyl H Cl —CH(CH₃)₂

29. t- bu- tyl H —CH₃

H 30. t- bu- tyl H —CH₃

H 31. t- bu- tyl H Cl CH₃

32. t- bu- tyl H Cl —CH(CH₃)₂

33. Cl CF₃ Cl —CH(CH₃)₂

34. Cl CF₃ Cl —CH(CH₃)₂

35. Cl CF₃ Cl —CH(CH₃)₂

36. Cl CF₃ Cl

H 37. Cl CF₃ Cl —CH(CH₃)₂ Br 38. Cl CF₃ Cl

H 39. Cl CF₃ CH₃

H 40. Cl CF₃ Cl

H 41. Cl CF₃ Cl

H 42. Cl CF₃ Cl

H 43. Cl CF₃ Cl

H 44. Cl CF₃ Cl

—CH(CH₃)₂ 45. Cl CF₃ Cl

46. Cl CF₃ Cl

CF₃ 47. Cl CF₃ Cl

H 48. Cl CF₃ Cl

49. Cl CF₃ Cl

50. Cl CF₃ Cl

CH₃ 51. Cl CF₃ Cl

52. Cl CF₃ Cl

53. Cl CF₃ Cl —CH(CH₃)₂ NH₂ 54. Cl CF₃ Cl

55. Cl CF₃ Cl

56. Cl CF₃ Cl

57. Cl CF₃ Cl

58. Cl Cl Cl

H 59. Cl Cl Cl

H 60. Cl CF₃ Cl

—C(CH₃)₃ 61. Cl CF₃ Cl

Br 62. Cl Cl Cl

H 63. Cl CF₃ Cl

Br 64. Cl CF₃ Cl

65. Cl CF₃ CH₃

66. Cl CF₃ Br

H 67. Cl CF₃ Br

H 68. Cl Cl Cl

69. CH₃ CF₃ Cl

70. Cl CF₃ CH₃

71. Cl CF₃ Cl —CH(CH₃)₂

72. Cl CF₃ Cl

H 73. Cl CF₃ Cl

H 74. Cl CF₃ Cl

H 75. Cl CF₃ Cl

H 76. Cl CF₃ Cl —CH₂CH₂CH₃ H 77. Cl CF₃ Cl —CH(CH₃)₂ Cl 78. Cl CF₃ Cl

H 79. Cl CF₃ Cl

H 80. Cl CF₃ Cl

CH₃ 81. Cl CF₃ Cl —CH(CH₃)₂ CH₂OH 82. Cl CF₃ Cl

CH₂OH 83. Cl CF₃ Cl

The above compounds and others within the scope of this invention can bemade and tested for activity using the following procedures.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (br, broad; s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet) and number of protons.Mass spectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microliter was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system

General Procedure A

Exemplified by 5-Chloro-3-(4-tert-butyl-phenylsulfonamido) picolinicacid

A 25 mL round-bottom flask was charged with3-amino-2-cyano-5-chloropyridine (1.04 g, 6.8 mmol),4-tert-butylbenzenesulfonyl chloride (2.09 g, 8.8 mmol), and pyridine (6mL). The resultant solution was heated to 70° C. and stirred for 5 h.The pyridine was removed in vacuo and 70% aqueous EtOH (20 mL) wasadded, followed by NaOH (3.20 g, 80 mmol). The mixture was stirred atreflux for 12 h. The solvent was subsequently removed in vacuo and ice(10 g) was added. The pH was adjusted to 2-3 with concentrated HCl. Theresultant aqueous solution was extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated under reduced pressure. The lightyellow solid was recrystallized from EtOAc/hexane (1:1) to afford thedesired acid as white needles (735 mg): MS (ES) M+H expected 369.1,found 369.0.

Example 2N-(5-Chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-4-tert-butyl-benzenesulfonamide

A 25 mL round-bottom flask vial was charged with5-chloro-3-(4-tert-butyl-phenylsulfonamido)picolinic acid (735 mg, 2mmol), BOP (1.77 g, 4 mmol), anhydrous hydrazine (1.2 mL), and anhydrousDMF (5 mL). The resultant solution was stirred for 2 h at roomtemperature and then diluted with water. The reaction mixture wassubsequently extracted with EtOAc, and the combined organics were washedwith brine, dried over MgSO₄, and concentrated under reduced pressure.The light yellow solid was recrystallized from EtOAc/hexane (1:1) toafford the desired hydrazide as a white solid (613 mg): MS (ES) M+Hexpected 383.1, found 383.0.

Example 34-tert-Butyl-N-(2-hydrazinocarbonyl-5-methyl-pyridin-3-yl)-benzenesulfonamide

4-tert-Butyl-N-(2-hydrazinocarbonyl-5-methyl-pyridin-3-yl)-benzenesulfonamidewas synthesized from 3-amino-5-methyl-pyridine-2-carbonitrile accordingto general procedure A.

General Procedure B

Exemplified by4-tert-Butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide

A 25 mL scintillation vial was charged with4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide(691 mg, 1.8 mmol), trimethyl orthoacetate (0.35 mL, 2.8 mmol),ethylamine (5 mL, 2.0 M), AcOH (3.0 mL), and dioxane (10 mL). The vialwas sealed, heated to 130° C., and stirred for three hours. Thevolatiles were then evacuated in vacuo and the residue was purified viaautomated silica gel chromatography and then preparative HPLC to afford4-tert-butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamideas a white powder: MS (ES) M+H expected 434.1, found 434.1.

General Procedure C

Exemplified by4-tert-Butyl-N-[6-chloro-2-(4-isopropyl-5-methoxymethyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide

A 25 mL scintillation vial was charged withN-isopropyl-2-methoxyacetamide (132 mg, 1.0 mmol), POCl₃ (0.19 mL, 2.0mmol), 2,6-lutidine (0.30 mL, 2.4 M), and CH₃CN (10 mL). The vial wassealed, heated to 40° C., and stirred for four hours. The volatiles werethen evacuated in vacuo and to the residue was added4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide(193 mg, 0.5 mmol), DIPEA (2.0 mL), and dioxane (2.0 mL). The vial wassealed, heated to 130° C., and stirred for two hours. The volatiles wasthen evacuated in vacuo, and the residue was purified via automatedsilica gel chromatography and then preparative HPLC to afford4-tert-butyl-N-[6-chloro-2-(4-isopropyl-5-methoxymethyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamideas a white powder: MS (ES) M+H expected 478.2, found 478.1.

General Procedure D

Exemplified by4-tert-Butyl-N-[5-chloro-2-(4-methyl-5-piperidin-4-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide

A 25 mL scintillation vial was charged with4-methylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (138 mg, 0.5mmol), POCl₃ (0.095 mL, 1.0 mmol), 2,6-lutidine (130 mg, 1.25 mmol), andCH₃CN (1.5 mL). The vial was sealed, heated to 40° C., and stirred forfour hours. The volatiles were then evacuated in vacuo and to theresultant residue was added4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide(193 mg, 0.5 mmol), DIPEA (0.5 mL), and dioxane (1.0 mL). The vial wassealed, heated to 130° C., and stirred for two hours. The volatiles werethen removed in vacuo and to the residue was added 3 mL of 33%hydrobromic acid in acetic acid. The vial was sealed and stirred for 3h. The volatiles were then evacuated in vacuo and the residue waspurified via preparatory HPLC to afford4-tert-butyl-N-[5-chloro-2-(4-methyl-5-piperidin-4-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamideas a white powder: MS (ES) M+H expected 489.2, found 488.5.

General Procedure E

Exemplified by5-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylicacid dimethylamide

A 25 mL scintillation vial was charged with5-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylicacid ethyl ester (prepared according to general procedure B, 11 mg, 0.02mmol), dimethylamine in THF (2 mL, 2.0 M), and KCN (1 mg, 0.01 mmol).The vial was sealed and stirred at 50° C. for 16 h. The volatiles werethen evacuated in vacuo and the residue was purified via preparatoryHPLC to afford4-tert-butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-enzenesultonamideas a white powder: MS (ES) M+H expected 505.2, found 505.5.

General Procedure F

Exemplified by4-tert-Butyl-N-{5-chloro-2-[5-(1-hydroxy-1-methyl-ethyl)-4-isopropyl-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-benzenesulfonamide

A 25 mL scintillation vial was charged with5-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylicacid ethyl ester (prepared according to general procedure B, 11 mg, 0.02mmol), methylmagnesium bromide in THF (0.2 mL, 3.0 M), andtetrahydrofuran (3 mL). The vial was sealed and stirred at 0° C. for 2h. The volatiles were then evacuated in vacuo and the residue waspurified via preparatory HPLC to afford4-tert-butyl-N-{5-chloro-2-[5-(1-hydroxy-1-methyl-ethyl)-4-isopropyl-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-benzenesulfonamideas a white powder: MS (ES) M+H expected 492.2, found 492.5.

General Procedure G

Exemplified byN-[2-(5-Amino-4-isopropyl-4H-[1,2,4]triazol-3-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide

Cyanogen bromide (110.9 mg, 1.05 mmol) was added to a solution of4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide(200 mg, 0.524 mmol) and potassium carbonate (145 mg, 1.05 mmol) indioxane (2 mL). The resultant mixture reaction was stirred for 18 h atroom temperature. Isopropyl amine (0.18 mL, 2.09 mmol) and acetic acid(0.15 mL) were subsequently added and the reaction was heated at 135° C.for 18 h. The crude mixture was partitioned between ethyl acetate andwater and the layers were separated. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine; dried over magnesiumsulfate, and concentrated in vacuo. The crude product was subsequentlypurified via flash column chromatography (10-100% ethyl acetate andhexane) followed by preparative HPLC (10-90% gradient of MeCN-water) toafford the title compound as a white solid: MS (ES) M+H expected 449.1,found 449.2.

General Procedure H

Exemplified byN-{5-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}-acetamide

A 25 mL scintillation vial was charged withN-[2-(5-amino-4-isopropyl-4H-[1,2,4]triazol-3-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide(9 mg, 0.02 mmol), acetyl chloride (7.9 mg, 0.1 mmol), triethylamine (10mg, 0.1 mmol), and tetrahydrofuran (2 mL). The vial was sealed andstirred at 0° C. for 2 h. The volatiles were then evacuated in vacuo andthe crude product was purified by flash column chromatography (10-100%ethyl acetate and hexane) followed by preparative HPLC (10-90% gradientof MeCN-water) to afford the title compound as a white solid: MS (ES)M+H expected 491.5, found 491.5.

General Procedure I

Exemplified by4-tert-Butyl-N-[5-chloro-2-(4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide

Step 1: A 25 mL scintillation vial was charged with4-tert-butyl-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide(191 mg, 0.50 mmol), trimethyl orthoformate (0.072 mL, 0.65 mmol), AcOH(0.60 mL), and dioxane (1.5 mL). The vial was sealed, heated to 110° C.,and stirred overnight. The following day, the intermediate methylcarbazate was observed at m/z 425 (via LCMS). 1-Boc-3-aminopyrrolidine(187 mg, 1.0 mmol) was subsequently added and the reaction continued at110° C. until LCMS analysis indicated consumption of the oxadiazoleintermediate. The volatiles were subsequently evacuated in vacuo and theresidue was purified via reverse-phase HPLC to provide3-{3-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-[1,2,4]triazol-4-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester as a white solid: MS (ES) M+H expected 561.1,found 561.1.

Step 2: The crude triazole, dissolved in a minimal amount of dioxane(0.3 mL), was treated with 4 N HCl in dioxane (1.0 mL). The vial wasflushed with nitrogen, stirred 5 h (the reaction was monitored by LCMS),and then concentrated in vacuo. Purification by preparative HPLCprovided 107 mg of the desired product,4-tert-butyl-N-[5-chloro-2-(4-pyrrolidin-3-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide,as a white solid: MS (ES) M+H expected 461.1, found 461.0.

1H-Pyrazol-4-ylamine

Step 1

Pyrazole (3.4 g, 50 mmol) was added in portions to conc sulfuric acid(25 mL) while keeping the reaction temperature below 40° C. To thissolution was then added 70% nitric acid (3.5 mL) dropwisely whilemaintaining the temperature below 55° C. The mixture was stirred at thistemperature for 4 hours. After cooling to room temperature, the mixturewas slowly poured into 500 grams of ice. The resultant mixture wasneutralized with 50% aqueous NaOH and the resulting slurry was dilutedwith 500 mL of ethyl acetate. This mixture was filtered and the filtratewas washed with water (300 ml), brine (300 ml), and dried over Na₂SO₄.The solution was concentrated, and the precipitate was collected anddried in vacuo to afford the title compound as white crystals. MS (ES)[M+H]⁺ expected 113.0, found 113.0.

Step 2

To a stirred mixture of iron (1.68 g, 30 mmol), ammonium chloride (540mg, 10 mmol), water (2 mL) and ethanol (8 mL) at 80° C. was added4-nitro-1H-pyrazol (1.13 g, 10 mmol) in portions. After completion ofaddition, the mixture was stirred at 80° C. for additional 2 hours.After cooling to room temperature, the mixture was diluted with ethylacetate, and the resultant mixture was filtered through a pad of celite.The filtrate was concentrated to afford the crude title compound whichwas used at next step without further purification. MS (ES) [M+H]⁺expected 84.0, found 84.0.

4-Chloro-N-{5-chloro-2-[4-(1H-pyrazol-4-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B. Thusly, amixture of trimethylorthoformate (53 mg, 0.50 mmol), acetonitrile (1.5mL), and 1H-pyrazol-4-ylamine (83 mg, crude, 1.0 mmol) was stirred at120° C. for 2 hours. After the mixture was cooled to room temperature,4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(42.8 mg, 0.10 mmol) and acetic acid (0.2 mL) was added and theresultant mixture was stirred at 120° C. for 2 hours. After evaporationof solvent under reduced pressure, the residue was further purifiedthrough automated normal-phase chromatography and dried (Lyophilizer) toafford title compound. ¹H NMR: (DMSO-d6, ppm): 8.90 (s, 1H), 8.08 (m,2H), 7.90 (m, 2H), 7.80 (m, 2H), 7.75 (m, 1H). MS (ES) [M+H]⁺ expected504.0, found 504.0.

4-Chloro-N-{5-chloro-2-[4-(2-methyl-2H-pyrazol-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B. using4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.234 mmol), trimethylorthoformate (80 mg, 0.75 mmol),acetonitrile (2 mL), 2-Methyl-2H-pyrazol-3-ylamine (48 mg, 0.50 mmol)and acetic acid (1.0 mL). MS (ES) [M+H]⁺ expected 518.0, found 518.0.

3-{3-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-butyricacid ethyl ester

A mixture of4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(42.8 mg, 0.10 mmol), trimethylorthoformate (53 mg, 0.50 mmol),acetonitrile (1.5 mL), 3-Amino-butyric acid ethyl ester (131 mg, 1.0mmol) and acetic acid (0.2 mL) was stirred at 120° C. for 2 hours. Afterevaporation of solvent under reduced pressure, the residue was furtherpurified through automated normal-phase chromatography and dried(Lyophilizer) to afford title compound. MS (ES) [M+H]⁺ expected 552.0,found 552.0.

4-Chloro-N-[5-chloro-2-(4-o-tolyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B using4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.234 mmol), trimethylorthoformate (80 mg, 0.75 mmol),acetonitrile (2 mL), 2-methylaniline (62 mg, 0.50 mmol) and acetic acid(1.0 mL). 1H NMR: (CD3OD, ppm): 8.82 (s, 1H), 8.40 (s, 1H), 8.27 (d,1H), 8.05 (m, 1H), 7.75 (d, 1H), 7.61 (s, 1H), 7.39 (m, 1H), 7.32 (m,1H), 7.25 (m, 2H), 2.15 (s, 3H). MS (ES) [M+H]⁺ expected 528.0, found528.0.

4-Chloro-N-{5-chloro-2-[4-(5-fluoro-2-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B using4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.234 mmol), trimethylorthoformate (80 mg, 0.60 mmol),acetonitrile (2 mL), 2-methoxyl-5-fluoroaniline (70 mg, 0.50 mmol) andacetic acid (1.0 mL). MS (ES) [M+H]⁺ expected 562.0, found 562.0.

4-Chloro-N-{5-chloro-2-[4-(3-hydroxy-1-methyl-propyl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

A mixture of3-{3-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-butyricacid ethyl ester (27 mg, 0.05 mmol), lithium borohydride (2.0M, 0.14 ml,0.28 mmol), 1.5 ml of THF and 0.02 ml of methanol was stirred at roomtemperature for 2 hours. The mixture was mixed with diluted HCl (1.0M),extracted with ethyl acetate, and the extracts were combined and washedwith brine and dried. After concentration the residue was purified byprep TLC to afford title compound as a white solid. 1H NMR: (DMSO-d6,ppm): 9.03 (s, 1H), 8.30 (m, 1H), 8.11 (m, 1H), 8.02 (m, 1H), 7.91 (m,1H), 7.83 (m, 1H), 3.28 (m, 1H), 3.19 (m, 2H), 1.91 (m, 2H), 1.42 (d,3H). MS (ES) [M+H]⁺ expected 510.0, found 510.0.

4-Chloro-N-[5-chloro-2-(5-hydroxymethyl-4-isoxazol-3-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of5-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-4-isoxazol-3-yl-4H-[1,2,4]triazole-3-carboxylicacid ethyl ester (28 mg, 0.05 mmol), 0.14 ml (0.28 mmol) of lithiumborohydride (2.0M) and 0.020 ml of methanol in 1.5 ml of THF was stirredat room temperature for 2 hours. The mixture was mixed with diluted HCl(1.0M), extracted with ethyl acetate, and the extracts were combined andwashed with brine and dried. After concentration the residue waspurified by prep TLC to afford title compound as a white solid. MS (ES)[M+H]⁺ expected 535.0, found 535.0

Ethyl5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate

To a vial containing ethyl(isopropylcarbamoyl)formate (160 mg, 1.0 mmol)was added thionyl chloride (1.0 mL, 13.8 mmol). The vial was capped witha teflon coated septa and heated to 80° C. for 5 h. After cooling toroom temperature, the volatiles were removed in vacuo. A solution of4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide(342 mg, 0.80 mmol) in toluene (3 mL) was added. The mixture was stirredat 40° C. for 16 h. After cooling to room temperature, the toluene wasremoved in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added,and the solution heated to 90° C. for 4 h. After cooling to roomtemperature, the volatiles were removed in vacuo, and the resultingresidue purified by flash chromatography on 4 g of silica gel (0→20%gradient of MeOH in DCM). The pure fractions were collected, and thesolvent removed in vacuo to afford the title compound (14 mg, 3% yield).HPLC retention time=3.17 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d,J=2.4, 1H), 8.19 (d, J=2.4, 1H), 8.04 (d, J=2.4, 1H), 7.89 (dd, J=2.0,8.4, 1H), 7.53 (d, J=8.0, 1H), 5.66 (sept, J=7.0, 1H), 4.52 (q, J=7.4,2H), 1.52 (d, J=7.0, 6H), 1.50 (t, J=7.4, 3H). MS (ES) [M+H]⁺ expected552.0, found 552.0.

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxamide

To a vial containing Ethyl5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate(59 mg, 0.1 mmol) was added THF (0.6 mL) and NH₄OH (0.2 mL). Thesolution was stirred at room temperature for 16 h. EtOAc (30 mL) wasadded. The organic phase washed with water (2×10 mL) and dried overNa₂SO₄. The volatiles were removed in vacuo. The resulting residue waspurified by preparative HPLC (20→95% gradient of MeCN—H₂O with 0.1% TFA)and the pure fractions lyophilized to afford the title compound (4.0 mg,8% yield). HPLC retention time=2.76 minutes. ¹H NMR (400 MHz, CDCl₃) δ8.41 (d, J=2.0, 1H), 8.16 (d, J=2.0, 1H), 8.05 (d, J=2.4, 1H), 7.85 (dd,J=2.4, 8.4, 1H), 7.53 (d, J=8.4, 1H), 5.75 (sept, J=6.8, 1H), 1.52 (d,J=6.8, 6H). MS (ES) [M+H]⁺ expected 523.0, found 522.9.

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide

To a vial containing ethyl5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate(57 mg, 0.1 mmol) was added Me₂NH in THF (1.0 mL of a 2.0M solution).The solution was stirred at room temperature for 16 h. EtOAc (30 mL) wasadded. The organic phase washed with water (2×10 mL) and dried overNa₂SO₄. The volatiles were removed in vacuo. The resulting residue waspurified by preparative HPLC (20→95% gradient of MeCN—H₂O with 0.1% TFA)and the pure fractions lyophilized to afford the title compound (3.7 mg,7% yield). HPLC retention time=2.91 minutes. ¹H NMR (400 MHz, CDCl₃) δ8.36 (d, J=2.0, 1H), 8.17 (d, J=2.4, 1H), 8.10 (d, J=2.4, 1H), 7.93 (dd,J=2.4, 8.4, 1H), 7.57 (d, J=8.4, 1H), 5.65 (sept, J=7.2, 1H), 3.20 (s,3H), 3.12 (s, 3H), 1.52 (d, J=7.2, 6H). MS (ES) [M+H]⁺ expected 551.1,found 551.0.

Ethyl5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxylate

To a vial equipped with a teflon coated septum and a nitrogen inlet wereadded ethyl(isoxazol-3-ylcarbamoyl)formate (370 mg, 2.0 mmol), MeCN (2mL) and 2,6-lutidine (0.6 mL, 5.2 mmol). The vial was cooled to 0° C.POCl₃ (0.4 mL, 4.3 mmol) was added, and the solution maintained at 0° C.for 30 min. The solution was then warmed to 40° C. for 3 h. Aftercooling to room temperature, solid4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)-benzenesulfonamide(500 mg, 1.2 mmol) was added, and the reaction heated to 80° C. for 1 h.The volatiles were removed in vacuo. Ethanol (9 mL) and triethylamine (1mL) were added, and the solution heated to 90° C. for 4 h. After coolingto room temperature, the volatiles were removed in vacuo, and theresulting residue purified by flash chromatography on 12 g of silica gel(50→100% gradient of EtOAc in hexanes). The pure fractions werecollected, and the solvent removed in vacuo to afford the title compound(139 mg, 20% yield). HPLC retention time=2.96 minutes. ¹H NMR (400 MHz,CDCl₃) δ 8.55 (d, J=2.0, 1H), 8.19 (d, J=2.0, 1H), 8.12 (d, J=2.4, 1H),7.98 (d, J=2.0, 1H), 7.90 (dd, J=2.4, 8.4, 1H), 7.58 (d, J=8.4, 1H),6.62 (d, J=2.0, 1H), 4.41 (q, J=7.2, 2H), 1.40 (t, J=7.2, 3H). MS (ES)[M+H]⁺ expected 577.0, found 577.0.

General Procedure J: Aminolysis of Triazole Esters

To a vial containing ethyl5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxylate(60 mg, 0.1 mmol) was added THF (1 mL) and the appropriate amine (20mmol). The solution was maintained for 18 h at room temperature. EtOAc(30 mL) was added. The organic phase was washed with water (2×10 mL) anddried over Na₂SO₄. The volatiles were removed in vacuo, and theresulting residue purified by flash chromatography on 12 g of silica gel(50→100% gradient of EtOAc in hexanes). The pure fractions werecollected, and the solvent removed in vacuo to afford the desiredcompound.

5-(3-(4-chloro-3-trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to general procedure J. HPLCretention time=2.59 minutes. ¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H),8.03 (d, J=2.0, 1H), 7.98 (br s, 1H), 7.84-7.87 (m, 2H), 7.66 (d, J=8.4,1H), 6.75 (d, J=2.0, 1H). MS (ES) [M+H]⁺ expected 548.0, found 547.9.

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to general procedure J. HPLCretention time=2.79 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (br s, 1H),8.18 (br s, 1H), 8.12 (br s, 1H), 7.93-7.95 (m, 2H), 7.59 (d, J=8.4,1H), 6.60 (br s, 1H), 3.34 (s, 3H), 3.06 (s, 3H). MS (ES) [M+H]⁺expected 576.0, found 576.0.

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-N-ethyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to general procedure J. HPLCretention time=2.77 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H),8.14-8.15 (m, 2H), 7.98 (s, 1H), 7.85 (d, J=8.4, 1H), 7.58 (d, J=8.4,1H), 6.43-6.51 (m, 1H), 3.41-3.48 (m, 2H), 1.24-1.28 (m, 3H). MS (ES)[M+H]⁺ expected 576.0, found 576.0.

(5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)(pyrolidin-1-yl)methanone

The title compound was prepared according to general procedure J. HPLCretention time=2.91 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H),8.14-8.19 (m, 2H), 7.92-7.97 (m, 2H), 7.58-7.60 (m, 1H), 6.65-6.66 (m,1H), 3.96-4.02 (m, 2H), 3.54-3.60 (m, 2H), 1.96-2.04 (m, 4H). MS (ES)[M+H]⁺ expected 602.0, found 602.0.

(5-(3-(4-chloro-3-(fluoromethyl)sulfonamido)-5-chloropyridin-2-yl)-4-isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)(morpholino)methanone

The title compound was prepared according to general procedure J. HPLCretention time=2.54 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=2.0,1H), 8.17-8.20 (m, 2H), 7.95-8.00 (m, 2H), 7.57-7.62 (m, 1H), 6.63-6.64(m, 1H), 3.69-3.96 (m, 4H). MS (ES) [M+H]⁺ expected 618.0, found 618.0.

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-N-ethyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to general procedure J. HPLCretention time=2.92 minutes. MS (ES) [M+H]⁺ expected 590.0, found 590.0.¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.14-8.16 (m, 2H), 7.99 (s, 1H),7.85 (d, J=8.0, 1H), 7.58 (d, J=8.0, 1H), 6.51-6.66 (m, 1H), 4.11-4.19(m, 1H), 1.27-1.29 (m, 6H).

5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-(isoxazol-3-yl)-N-methyl-N-ethyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared according to general procedure J. HPLCretention time=2.87 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.48 (m,1H), 8.15-8.21 (m, 2H), 7.95-7.99 (m, 2H), 7.61 (d, J=8.4, 1H),6.61-6.62 (m, 1H), 3.70 and 3.51 (q, J=7.0, 2H), 3.31 and 3.03 (s, 3H),1.36 and 1.18 (t, J=7.0, 3H), MS (ES) [M+H]⁺ expected 590.0, found590.0.

N-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloro-2-(4-(isoxazol-3-yl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-amine

To a vial equipped with a teflon coated septum and a nitrogen inlet wereadded N-(isoxazol-3-yl)-2-methoxyacetamide (330 mg, 2.1 mmol), MeCN (4mL) and 2,6-lutidine (0.5 mL, 4.3 mmol). The vial was cooled to 0° C.POCl₃ (0.25 mL, 2.7 mmol) was added, and the solution maintained at 0°C. for 30 min. The solution was then warmed to 80° C. for 1 h. Aftercooling to room temperature, solid4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide(430 mg, 1.0 mmol) was added, and the reaction heated to 80° C. for 1 h.The volatiles were removed in vacuo. Ethanol (9 mL) and triethylamine (1mL) were added, and the solution heated to 90° C. for 4 h. After coolingto room temperature, the volatiles were removed in vacuo, and theresulting residue purified by flash chromatography on 12 g of silica gel(0→40% gradient of MeOH in DCM). The pure fractions were collected, andthe solvent removed in vacuo to afford the title compound (55 mg, 10%yield). HPLC retention time=2.82 minutes. MS (ES) [M+H]⁺ expected 549.0,found 549.0.

N-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloro-2-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-amine

To a vial equipped with a teflon coated septum and a nitrogen inlet wereadded4-chloro-N-[5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide(50 mg, 0.10 mmol) and DCM (0.2 mL). The reaction mixture was cooled to5° C. N-Chlorosuccinimide (16 mg, 0.12 mmol) was added, and the reactionwarmed to room temperature. After 48 h, EtOAc (10 mL) was added. Thesolution was stirred with 5% aq. NaHSO₃ solution (10 mL) for 15 min. Thelayers were then partitioned. The organic phase was washed with water(1×5 mL) and dried over Na₂SO₄. The volatiles were removed in vacuo. Theresulting residue was purified by preparative HPLC (20→95% gradient ofMeCN—H₂O with 0.1% TFA) and the pure fractions lyophilized to afford thetitle compound (10 mg, 19% yield). HPLC retention time=3.13 minutes. ¹HNMR (400 MHz, CDCl₃) δ 8.47 (s, 1H), 8.31 (s, 1H), 8.11 (d, J=2.0, 1H),7.94 (dd, J=2.0, 8.0, 1H), 7.57 (d, J=8.0, 1H), 5.57 (sept, J=6.4, 1H),1.52 (d, J=6.4, 6H). MS (ES) [M+H]⁺ expected 514.0, found 513.9.

4-Chloro-N-{5-chloro-2-[4-(2-hydroxy-1-methyl-ethyl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B. ¹H NMR(400 MHz, DMSO-d⁶) δ 8.90 (s, 1H), 8.51 (m, 1H), 8.05 (m, 1H), 7.99 (m,2H), 7.85 (d, 1H), 5.19 (m, 1H), 4.98 (brs., 1H, —OH), 3.70 (dd, 1H),3.40 (dd, 1H), 1.30 (s, 3H). MS (ES) [M+H]⁺ expected 496.0, found 495.9.

4-Chloro-N-{5-chloro-2-[4-(2-dimethylamino-1-methyl-ethyl)-4H-[1,2,4]-triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B. ¹H NMR(400 MHz, CD₃OD) δ8.95 (s, 1H), 8.52 (d, 1H), 8.25 (d, 1H), 8.10 (m,1H), 8.00 (dd, 1H), 7.74 (d, 1H), 6.11 (m, 1H), 3.86 (dd, 1H), 3.58 (d,1H), 2.98 (s, 6H), 1.47 (d, 3H). MS (ES) [M+H]⁺ expected 523.0, found523.0.

4-Chloro-N-[5-chloro-2-(4-piperidin-4-yl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general Method B. MS (ES)[M+H]⁺ expected 521.0, found 521.0.

3-{3-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-4-methoxy-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared according to general Method B. MS (ES)[M+H]⁺ expected 637.0, found 637.0.

4-Chloro-N-{5-chloro-2-[4-(4-methoxy-pyrrolidin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

To3-{3-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-4-methoxy-pyrrolidine-1-carboxylicacid tert-butyl ester (71 mg, 0.11 mmol) was added 1:1 mixture ofTFA-CH₂Cl₂ (2 mL) at room temperature and stirred for 2 h. Solvents wereevaporated, 1:1 mixture of CH₃CN—H₂O (5 mL) and lyophilized to obtain4-chloro-N-{5-chloro-2-[4-(4-methoxy-pyrrolidin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamideas a white solid in quantitative yield. MS (ES) [M+H]⁺ expected 537.0,found 537.0.

4-Chloro-N-{5-chloro-2-[5-isopropyl-4-(1H-pyrazol-3-yl)-4H-[1,2,4]triazol-3-yl]pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general procedure C. ¹H NMR(400 MHz, CDCl₃) δ 8.32 (m, 2H), 8.05 (s, 1H), 7.95 (m, 1H), 7.62 (m,1H), 7.58 (m, 1H), 6.28 (s, 1H), 2.90 (m, 1H), 1.28 (m, 6H). MS (ES)[M+H]⁺ expected 546.0, found 545.9.

4-Chloro-N-{5-chloro-2-[5-cyclopropyl-4-(1H-pyrazol-3-yl)-4H-[1,2,4]-triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general procedure C. ¹H NMR(400 MHz, CDCl₃) δ 8.15 (m, 2H), 7.95 (m, 2H), 7.70 (s, 1H), 7.58 (d,1H), 6.28 (s, 1H), 3.05 (m, 1H), 1.28 (m, 4H). MS (ES) [M+H]⁺ expected544.0, found 543.9.

N-{2-[5-tert-Butyl-4-(1H-pyrazol-3-yl)-4H-[1,2,4]triazol-3-yl]-5-chloro-pyridin-3-yl}-4-chloro-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to general procedure C. MS(ES) [M+H]⁺ expected 560.0, found 560.0.

5-[3-(4-Chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridin-2-yl]-4-isoxazol-3-yl-4H-[1,2,4]triazole-3-carboxylicacid ethyl ester

The title compound was prepared according to general procedure C. MS(ES) [M+H]⁺ expected 557.0, found 556.9.

5-[3-(4-Chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridin-2-yl]-4-isoxazol-3-yl-4H-[1,2,4]-triazole-3-carboxylicacid amide

The title compound was prepared according to general procedure J. ¹H NMR(400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.08 (s, 1H), 7.91 (m, 2H), 7.80 (d,1H), 7.55 (d, 1H), 6.61 (s, 1H), 2.34 (s, 3H). MS (ES) [M+H]⁺ expected528.0, found 528.0.

General Method K.4-Chloro-N-[5-chloro-3-E4-methyl-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide

A 35 mL scintillation vial was charged withN-(4-chloro-2-hydrazinecarbonyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide(MS, 409 [M+H]⁺) (205 mg, 0.5 mmol), ethyl triethoxyacetate (J. Am.Chem. Soc. 1951, 73, 5168-5169.) (165 mg, 0.75 mmol), and anhydrous MeCN(3 mL). The resultant mixture was heated to 65° C. and stirred for 1 h.After cooling to room temperature, 3-aminoisoxazole (85 mg, 1 mmol) wasadded followed by AcOH (0.2 mL), and mixture was heated to 65° C. for 30min and then to 135° C. and stirred for 2 h. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was purified through automated normal-phasechromatography (10% to 100% gradient of EtOAc-Hexane) and dried(Lyophilizer) to afford the desired triazole ester (MS (ES) [M+H]⁺expected 557.0, found 557.0), which was used directly for the next step.

To the above ester in THF (2 mL) was added aqueous ammonia (28%, 1 mL),and the resultant mixture was stirred at room temperature for 3 h. Thereaction mixture was diluted with 1N HCl and extracted EtOAc (50 mL×2),the combined organic layer was concentrated under reduced pressure. Theresidue was purified through automated normal-phase chromatography (10%to 100% gradient of EtOAc-Hexane) and dried (Lyophilizer) to afford thetitle compound. ¹H NMR (400 MHz, d⁶-DMSO) δ 11.0 (br, 1H), 8.98 (d, 1H),8.60 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.95 (m, 2H), 7.87 (s, 1H),7.61 (d, 1H), 6.78 (d, 1H), 2.49 (s, 3H). MS (ES) [M+H]⁺ expected 528.0,found 528.0.

5-(5-Chloro-3-(3,4-dichlorophenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared by procedure analogous to that describedin Example [00458] using3,4-dichloro-N-(4-chloro-2-hydrazinecarbonyl)pyridine-3-yl)benzenesulfonamide(200 mg, 0.5 mmol) (MS, 396.9 [M+H]⁺), ethyl triethoxyacetate (J. Am.Chem. Soc. 1951, 73, 5168-5169.) (165 mg, 0.75 mmol), and3-aminoisoxazole (85 mg, 1 mmol). ¹H NMR (400 MHz, d⁶-DMSO) δ 8.82 (d,1H), 8.47 (s, 1H), 7.79 (s, 1H), 7.67 (d, 1H), 7.59 (s, 1H), 7.56 (s,1H), 7.40 (dd, 1H), 7.23 (d, 1H), 6.64 (d, 1H). MS (ES) [M+H]⁺ expected514.0, found 513.9.

N-[2-(5-bromo-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

4-Chloro-N-[5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide(80 mg) in CCl4/DCM (3 mL/1 mL) was charged with NBS (30 mg). Theresulting mixture was stirred at room temperature for 6 h. The reactionmixture was diluted with sat NaHCO3 and extracted EtOAc (50 mL×2), thecombined organic layer was concentrated under reduced pressure. Theresidue was purified through automated normal-phase chromatography (10%to 100% gradient of EtOAc-Hexane), and followed by preparative HPLC (10%to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 11.6 (br, 1H), 8.60 (d, 1H),8.46 (s, 1H), 8.27 (s, 1H), 8.19 (d, 1H), 7.98 (dd, 1H), 7.62 (d, 1H),6.63 (d, 1H). MS (ES) [M+H]⁺ expected 584.0, found 584.0.

N-[2-(5-bromo-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example [00463] using4-Chloro-N-[5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) 8.35 (s, 1H), 8.26 (s, 1H), 8.12 (d, 1H), 7.92(dd, 1H), 7.56 (d. 1H), 5.50 (m, 1H), 1.48 (d, 6H). MS (ES) [M+H]⁺expected 559.9, found 559.9.

N-[2-(4-(4-bromo-1H-pyrazole-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-3,4-dichlorobenzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example [00463] usingN-[2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-3,4-dichlorobenzenesulfonamide.¹H NMR (400 MHz, CDCl₃) 11.67 (br, 1H), 10.20 (br, 1H), 8.27 (s, 1H),8.16 (d, t H), 7.95 (d, 1H), 7.90 (d, 1H), 7.68 (dd, 2H), 7.46 (d, 1H).MS (ES) [M+H]⁺ expected 549.9, found 549.9.

N-[2-(5-bromo-4-(4-bromo-1H-pyrazole-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-3,4-dichlorobenzenesulfonamide

The same experiment described in Example [00467] also produced the titlecompound. ¹H NMR (400 MHz, CDCl₃) 11.60 (br, 1H), 10.25 (br, 1H), 8.30(s, 1H), 8.22 (s, 1H), 7.72 (d, 1H), 7.68 (dd, 2H), 7.49 (d, 1H). MS(ES) [M+H]⁺ expected 629.8, found 629.8.

N-[2-(4-(4-bromo-1H-pyrazole-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example [00463] using4-chloro-N-[5-Chloro-2-(5-methyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide(MS, 518.0 [M+H]⁺). ¹H NMR (400 MHz, CDCl₃) 8.12 (m, 2H), 7.94 (dd, 1H),7.88 (d, 1H), 7.72 (s, 1H), 7.56 (d, 1H), 2.40 (s, 3H). MS (ES) [M+H]⁺expected 597.9, found 597.9.

N-[2-(4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-trifluoromethyl)benzenesulfonamide

To a solution of4-dichloro-N-(4-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide(210 mg, 0.5 mmol) in DCM (10 mL) was added TEA (0.2 mL), followed bytrifluoroacetic acid anhydride (210 mg, 1 mmol).

The resulting mixture was stirred at room temperature for 6 h. Thereaction mixture was diluted with sat NaHCO₃ and extracted DCM (50mL×2), the combined organic layer was concentrated under reducedpressure. The residue was purified through automated normal-phasechromatography (10% to 100% gradient of EtOAc-Hexane) to afford theintermediate oxodiazole ((MS (ES) [M+H]⁺ expected 506.9, found 506.9)which was used directly for the next step.

A 35 mL scintillation vial was charged with the above oxodiazole (110mg, 0.2 mmol), anhydrous MeCN (3 mL), 3-aminopyrazole (45 mg, 0.5 mmol)was added followed by CSA (10 mg, cat), and mixture was heated to 135°C. and stirred for 2 h. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue waspurified through automated normal-phase chromatography (10% to 100%gradient of EtOAc-Hexane) and dried in vacuo to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 10.15 (br, 1H), 8.18 (d, 1H), 8.10(d, 1H), 7.96 (d, 1H), 7.90 (dd, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 6.40(d, 1H). (MS (ES) [M+H]⁺ expected 572.0, found 572.0).

N-[2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-3,4-dichlorobenzenesulfonamide

The titled compound was prepared according to general Method C describedin Example 5 using3,4-dichloro-N-(4-chloro-2-hydrazinecarbonyl)pyridine-3-yl)benzenesulfonamideand 3-aminopyrazole: ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 8.12 (d1H), 8.02 (d, 1H), 7.88 (d, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.46 (d,1H), 6.25 (d, 1H). MS (ES) [M+H⁺ expected 470.0, found 470.0.

3,4-dichloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-benzenesulfonamide

The titled compound was prepared according to general Method B using3,4-dichloro-N-(4-chloro-2-hydrazinecarbonyl)pyridine-3-yl)benzenesulfonamideand 3-aminoisoxazole. MS (ES) (M+H)⁺ expected 471.0, found 470.9.

N-[2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-bromopyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using3,4-dichloro-N-(4-bromo-2-hydrazinecarbonyl)pyridine-3-yl)benzenesulfonamide(MS, 474.9 (M+H)) and 3-aminopyrazole: ¹H NMR (400 MHz, CDCl₃) δ 8.34(s, 1H), 8.30 (d, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.90 (dd, 1H), 7.61(d, 1H), 7.54 (d, 1H), 6.25 (d, 1H). MS (ES) [M+H]⁺ expected 549.9,found 549.9.

N-(5-bromo-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using3,4-dichloro-N-(4-bromo-2-hydrazinecarbonyl)pyridin-3-yl)benzenesulfonamideand 3-aminoisoxazole. MS (ES) [M+H]⁺ expected 550.9, found 550.9.

N-[2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-methylpyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using4-chloro-N-(2-(hydrazinecarbonyl)-5-methylpyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide(MS, 409 (M+H)) and 3-aminopyrazole: ¹H NMR (400 MHz, CDCl₃) δ 11.05(br, 1H), 8.41 (d, 1H), 7.98 (m, 3H), 7.84 (d, 2H), 7.61 (dd, 1H), 7.49(d. 1H), 6.22 (d, 1H), 2.36 (s, 3H). MS (ES) [M+H]⁺ expected 484.0,found 484.0.

N-[2-(4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using4-chloro-N-(2-(hydrazinecarbonyl)-5-chloropyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamideand 3-amino-4-bromopyrazole: ¹H NMR (400 MHz, CDCl₃) δ 11.70 (br, 1H),8.30 (s, 1H), 8.18 (d, 1H), 8.13 (d, 1H), 7.98 (d, 1H), 7.95 (dd, 1H),7.68 (s, 1H), 7.55 (d. 1H). MS (ES) [M+H]⁺ expected 583.9, found 583.9.

4-Chloro-N-[5-chloro-2-(4-(3-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using4-chloro-N-(2-(hydrazinecarbonyl)-5-chloropyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamideand 4-amino-2-methylpyrazole: ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, 2H),8.12 (dd, 1H), 8.03 (dd, 1H), 7.97 (dd, 1H), 7.57 (d, 1H), 7.47 (d. 1H),1.98 (s, 3H). MS (ES) [M+H]⁺ expected 518.0, found 518.0.

4-Chloro-N-[5-chloro-2-(4-(4-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide

The titled compound was prepared according to general Method B using4-chloro-N-(2-(hydrazinecarbonyl)-5-chloropyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamideand 3-amino-4-hydroxymethylpyrazole((MS, 409 [M+H]⁺, which was generatedin situ by reduction of ethyl 3-amino-1H-pyrazole-4-carboxylate usingLAH in THF): ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.16 (d, 1H), 8.13(d, 1H), 7.97 (d, 1H), 7.94 (dd, 1H), 7.56 (d, 1H), 7.42 (d. 1H), 1.65(s, 3H). MS (ES) [M+H]⁺ expected 518.0, found 518.0.

N-[2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide

A 35 mL scintillation vial was charged with4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide(500 mg, 1.1 mmol), cyanogenbromide (200 mg, 2.0 mmol) anhydrous MeCN (5mL). The resultant mixture was heated to 65° C. and stirred for 2 h.After cooling to room temperature, isopropylamine (500 mg, 8.2 mmol) wasadded followed by AcOH (0.5 mL) and the mixture was heated to 135° C.and stirred for 2 h. After cooling to room temperature, reaction mixturewas concentrated under reduced pressure. The residue was furtherpurified through automated normal-phase chromatography (10% to 100%gradient of EtOAc-Hexane) and followed by preparative HPLC (10% to 90%gradient of MeCN-water) and dried (Lyophilizer) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) 8.28 (d, 1H), 8.18 (d, 1H), 8.10 (d,1H), 7.90 (dd, 1H), 7.58 (d. 1H), 4.32 (br, 1H), 3.88 (m, 1H), 1.34 (d(d, 6H). MS (ES) [M+H]⁺ expected 495.0, found 495.0.

4-Chloro-N-[5-chloro-2-(5-(dimethylamino)methyl-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide

A 25 mL scintillation vial was charged with4-Chloro-N-[5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide(60 mg, 0.14 mmol), Eschenmoser salt (25 mg, 0.2 mmol) and anhydrous DMF(2 mL). The resultant mixture was heated to 130° C. and stirred for 3 h.After cooling to room temperature, the residue was purified throughpreparative HPLC (10% to 90% gradient of MeCN-water) and dried(Lyophilizer) to afford the title compound. ¹H NMR (400 MHz, CDCl₃) 8.35(d, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.50 (d. 1H), 5.40(m, 1H), 3.65 (s, 2H), 2.23 (s, 6H), 1.42 (d, 6H). MS (ES) [M+H]⁺expected 537.0, found 537.0.

4-Chloro-N-[5-chloro-2-(5-(methoxymethyl)-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide

To a solution of4-dichloro-N-(4-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide(210 mg, 0.5 mmol) in THF (10 mL) under ice-bath was added TEA (0.2 mL),followed by methoxyactetyl chloride (0.6 mmol). The resulting mixturewas stirred at room temperature for 3 h. The reaction mixture wasdiluted with sat NaHCO₃ and extracted EtOAc (50 mL×2), the combinedorganic layer was concentrated under reduced pressure. The residue wasdissolved in anhydrous MeCN (3 mL) and transferred to a 35 mLscintillation vial, and then added POCl₃ (0.1 mL). The resultant mixturewas heated to 135° C. and stirred for 2 h to form the intermediateoxodiazole ((MS (ES) [M+H]⁺ expected 483.0, found 482.9).

After cooling to room temperature, 3-aminopyrazole (84 mg, 1.0 mmol) wasadded followed by CSA (10 mg, cat), and mixture was heated to 140° C.and stirred for 2 h. After cooling to room temperature, the reactionmixture was concentrated under reduced pressure. The residue waspurified through automated normal-phase chromatography (10% to 100%gradient of EtOAc-Hexane) preparative HPLC (10% to 90% gradient ofMeCN-water) and dried (Lyophilizer) to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.16 (d, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.92 (dd,1H), 7.68 (d, 1H), 7.55 (d, 1H), 6.33 (d, 1H), 4.52 (s, 2H), 3.32 (s,3H). MS (ES) [M+H]⁺ expected 548.0, found 548.0.

4-Chloro-N-[5-chloro-2-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-trifluoromethyl)benzenesulfonamide

The title compound was prepared according to the procedure described inExample [00473] using aniline. MS (ES) [M+H]⁺ expected 582.0, found581.9.

The compounds in Table 2 were prepared by the indicated generalprocedure described above. MS (ES) [M+H]⁺ data was collected andcompared to the expected value to confirm the identity of the compound.TABLE 2 Compounds prepared by General Procedures and MS Data SyntheticObserved STRUCTURE Method Molecular Ion (M + 1)

B 448.1

B 420.0

B 434.1

C 483.0

C 483.1

D 475.1

B 446.1

B 434.1

C 450.2

C 478.1

B 420.0

B 406.1

D 490.1

B 506.0

E 491.1

F 492.1

E 505.1

G 449.1

C 520.1

H 491.1

C 464.0

B 541.2

I 441.1

B 455.1

I 461.0

I 475.0

B 468.0

B 486.0

C 459.0

C 448.0

D 447.7

B 448.1

Measuring Efficacy of Chemokine Modulators

In Vitro Assays

A variety of assays can be used to evaluate the compounds providedherein, including signaling assays, migration assays, ligand bindingassays, and other assays of cellular response. Chemokine receptorsignaling assays can be used to measure the ability of a compound, suchas a potential CCR2 antagonist, to block CCR2 ligand-(e.g.MCP-1)-induced signaling or a potential CCR9 antagonist, to block CCR9ligand-(e.g. TECK)-induced signaling. A migration assay can be used tomeasure the ability of a compound of interest, such as a possiblechemokine antagonist, to block chemokine-mediated cell migration invitro. The latter is believed to resemble chemokine-induced cellmigration in vivo. A ligand binding assay can be used to measure theability of a compound, such as a potential CCR2 antagonist, to block theinteraction of MCP-1 with its receptor or a potential CCR9 antagonist,to block the interaction of TECK with its receptor.

In a suitable assay, a chemokine protein (whether isolated orrecombinant) is used which has at least one property, activity, orfunctional characteristic of a mammalian chemokine protein. The propertycan be a binding property (to, for example, a ligand or inhibitor), asignaling activity (e.g., activation of a mammalian G protein, inductionof rapid and transient increase in the concentration of cytosolic freecalcium ion), cellular response function (e.g., stimulation ofchemotaxis or inflammatory mediator release by leukocytes), and thelike.

The assay can be a cell-based assay that utilizes cells stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence that encodes the chemokine receptor. Cell linesnaturally expressing the chemokine can also be used. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with a putative agent under conditions appropriate forbinding to occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol (for example, relative to background in the absence of aputative agent, or relative to a known ligand). Optionally, a cellularfraction, such as a membrane fraction, containing the receptor can beused in lieu of whole cells.

Detection of binding or complex formation can be detected directly orindirectly. For example, the putative agent can be labeled with asuitable label (e.g., fluorescent label, chemiluminescent label, isotopelabel, enzyme label, and the like) and binding can be determined bydetection of the label. Specific and/or competitive binding can beassessed by competition or displacement studies, using unlabeled agentor a ligand (e.g., MCP-1 or TECK) as a competitor.

Binding inhibition assays can be used to evaluate the present compounds.In these assays, the compounds are evaluated as inhibitors of ligandbinding using, for example, MCP-1 or TECK. In one embodiment, the CCR2receptor is contacted with a ligand such as MCP-1 and a measure ofligand binding is made. The receptor is then contacted with a test agentin the presence of a ligand (e.g., MCP-1) and a second measurement ofbinding is made. In another embodiment, the CCR9 receptor is contactedwith a ligand such as TECK and a measure of ligand binding is made. Thereceptor is then contacted with a test agent in the presence of a ligand(e.g., TECK) and a second measurement of binding is made. A reduction inthe extent of ligand binding is indicative of inhibition of binding bythe test agent. The binding inhibition assays can be carried out usingwhole cells which express the chemokine, or a membrane fraction fromcells which express the chemokine.

The binding of a G protein coupled receptor by, for example, an agonist,can result in a signaling event by the receptor. Accordingly, signalingassays can also be used to evaluate the compounds of the presentinvention and induction of signaling function by an agent can bemonitored using any suitable method. For example, G protein activity,such as hydrolysis of GTP to GDP, or later signaling events triggered byreceptor binding can be assayed by known methods (see, for example,PCT/US97/15915; Neote et al., Cell, 72:415425 (1993); Van Riper et al.,J. Exp. Med., 177:851-856 (1993) and Dahinden et al., J. Exp. Med.,179:751-756 (1994)).

Chemotaxis assays can also be used to assess receptor function andevaluate the compounds provided herein. These assays are based on thefunctional migration of cells in vitro or in vivo induced by an agent,and can be used to assess the binding and/or effect on chemotaxis ofligands, inhibitors, or agonists. A variety of chemotaxis assays areknown in the art, and any suitable assay can be used to evaluate thecompounds of the present invention. Examples of suitable assays includethose described in PCT/US97/15915; Springer et al., WO 94/20142; Bermanet al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.Immunol., 146:4149-4156 (1991)).

Calcium signaling assays measure calcium concentration over time,preferably before and after receptor binding. These assays can be usedto quantify the generation of a receptor-signaling mediator, Ca⁺⁺,following receptor binding (or absence thereof). These assays are usefulin determining the ability of a compound, such as those of the presentinvention, to generate the receptor signaling mediator by binding to areceptor of interest. Also, these assays are useful in determining theability of a compound, such as those of the present invention, toinhibit generation of the receptor signaling mediator by interferingwith binding between a receptor of interest and a ligand.

In calcium signaling assays used to determine the ability of a compoundto interfere with binding between a chemokine receptor and a knownchemokine ligand, chemokine receptor-expressing cells (CCR2-expressingcells such as THP-1 cells or CCR9-expressing cells such as T cell lineMOLT-4 cells) are first incubated with a compound of interest, such as apotential chemokine antagonist, at increasing concentrations. The cellnumber can be from 10⁵ to 5×10⁵ cells per well in a 96-well microtiterplate. The concentration of the compound being tested may range from 0to 100 μM. After a period of incubation (which can range from 5 to 60minutes), the treated cells are placed in a Fluorometric Imaging PlateReader (FLIPR®) (available from Molecular Devices Corp., Sunnyvale,Calif.) according to the manufacturer's instruction. The FLIPR® systemis well known to those skilled in the art as a standard method ofperforming assays. The cells are then stimulated with an appropriateamount of the chemokine ligand (MCP-1 for CCR2 or TECK for CCR9) at5-100 nM final concentration, and the signal of intracellular calciumincrease (also called calcium flux) is recorded. The efficacy of acompound as an inhibitor of binding between the chemokine and the ligandcan be calculated as an IC₅₀ (the concentration needed to cause 50%inhibition in signaling) or IC₉₀ (at 90% inhibition).

In vitro cell migration assays can be performed (but are not limited tothis format) using the 96-well microchamber (called ChemoTX™). TheChemoTX™ system is well known to those skilled in the art as a type ofchemotactic/cell migration instrument. In this assay, CCR2-expressingcells (such as THP-1) or CCR9-expressing cells (such as MOLT-4) arefirst incubated with a compound of interest, such as a possible CCR2 orCCR9 antagonist, respectively, at increasing concentrations. Typically,fifty thousand cells per well are used, but the amount can range from10³-10⁶ cells per well. The chemokine ligand (for example, CCR2 ligandMCP-1, typically at 0.1 nM (but can range from 5-100 nM); or CCR9 ligandTECK, typically at 50 nM (but can range from 5-100 nM)), is placed atthe lower chamber and the migration apparatus is assembled. Twentymicroliters of test compound-treated cells are then placed onto themembrane. Migration is allowed to take place at 37° C. for a period oftime, typically 1.5 hours for CCR2 or 2.5 hours for CCR9. At the end ofthe incubation, the number of cells that migrated across the membraneinto the lower chamber is then quantified. The efficacy of a compound asan inhibitor of chemokine-mediated cell migration is calculated as anIC₅₀ (the concentration needed to reduce cell migration by 50%) or IC₉₀(for 90% inhibition).

In Vivo Efficacy Models for Human IBD

T cell infiltration into the small intestine and colon have been linkedto the pathogenesis of human inflammatory bowel diseases which includeCoeliac disease, Crohn's disease and ulcerative colitis. Blockingtrafficking of relevant T cell populations to the intestine is believedto be an effective approach to treat human IBD. CCR9 is expressed ongut-homing T cells in peripheral blood, elevated in patients with smallbowel inflammation such as Crohn's disease and Coeliac disease. CCR9ligand TECK is expressed in the small intestine. It is thus believedthat this ligand-receptor pair plays a role in IBD development bymediating migration of T cells to the intestine. Several animal modelsexist and can be used for evaluating compounds of interest, such aspotential CCR9 antagonists, for an ability to affect such T cellmigration and/or condition or disease, which might allow efficacypredictions of antagonists in humans.

Animal Models with Pathology Similar to Human Ulcerative Colitis

A murine model described by Panwala and coworkers (Panwala, et al., JImmunol, 161(10):5733-44 (1998)) involves genetic deletion of the murinemulti-drug resistant gene (MDR). MDR knockout mice (MDR−/−) aresusceptible to developing a severe, spontaneous intestinal inflammationwhen maintained under specific pathogen-free facility conditions. Theintestinal inflammation seen in MDR−/− mice has a pathology similar tothat of human inflammatory bowel disease (IBD) and is defined by Th1type T cells infiltration into the lamina propria of the largeintestine.

Another murine model was described by Davidson et al., J. Exp. Med.,184(1):241-51(1986). In this model, the murine IL-10 gene was deletedand mice rendered deficient in the production of interleukin 10(IL-10−/−). These mice develop a chronic inflammatory bowel disease(IBD) that predominates in the colon and shares histopathologicalfeatures with human IBD.

Another murine model for IBD has been described by Powrie et al., IntImmunol., 5(11):1461-71 (1993), in which a subset of CD4+ T cells(called CD45RB(high)) from immunocompetent mice are purified andadoptively transferred into immunodeficient mice (such as C.B-17 scidmice). The animal restored with the CD45RBhighCD4+ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates in the colon, pathologically similar with human IBD.

Murine Models with Pathology Similar to Human Crohn's Disease

The TNF ARE(−/−) model. The role of TNF in Crohn's disease in human hasbeen demonstrated more recently by success of treatment using anti-TNFalpha antibody by Targan et al., N. Engl. J. Med., 337(15):1029-35(1997). Mice with aberrant production of TNF-alpha due to geneticalteration in the TNF gene (ARE−/−) develop Crohn's-like inflammatorybowel diseases (see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).

The SAMP/yit model. This is model described by Kosiewicz et al., J.Clin. Invest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit,spontaneously develops a chronic inflammation localized to the terminalileum. The resulting ileitis is characterized by massive infiltration ofactivated T lymphocytes into the lamina propria, and bears a remarkableresemblance to human Crohn's disease.

Examples of in Vitro Assays

Reagents

THP-1 cells and MOLT-4 cells were obtained from the American TypeCulture Collection (Manassas, Va.) and cultured in RPMI tissue culturemedium supplemented with 10% fetal calf serum (FCS) in a humidified 5%CO₂ incubator at 37° C. Recombinant human chemokine proteins MCP-1 andTECK were obtained from R&D Systems (Minneapolis, Minn.). ¹²⁵I-labeledMCP-1 protein was obtained from Amersham (Piscataway, N.J.). ChemoTX®chemotaxis microchambers were purchased from Neuro Probe (Gaithersburg,Md.). CyQUANT® cell proliferation kits were purchased from MolecularProbes (Eugene, Oreg.). Calcium indicator dye Fluo-4 AM was purchasedfrom Molecular Devices (Mountain View, Calif.).

Conventional Migration Assay

Conventional migration assay was used to determine the efficacy ofpotential receptor antagonists in blocking migration mediated throughchemokines (such as CCR2 or CCR9). This assay was routinely performedusing the ChemoTX® microchamber system with a 5-μm pore-sizedpolycarbonate membrane. To begin such an assay, chemokine expressingcells (such as THP-1 cells for CCR2 assay or MOLT-4 cells for CCR9assay) were harvested by centrifugation of cell suspension at 1000 RPMon a GS-6R Beckman centrifuge. The cell pellet was resuspended inchemotaxis buffer (HBSS with 0.1% BSA) at 10×10⁶ cells/mL for CCR2 assay(5×10⁶ cells/mL for CCR9 assay). Test compounds at desiredconcentrations were prepared from 10 mM stock solutions by serialdilutions in chemotaxis buffer. An equal volume of cells and compoundswere mixed and incubated at room temperature for 15 minutes. Afterwards,20 μL of the mixture was transferred onto the porous membrane of amigration microchamber, with 29 μL of chemokine ligand (0.1 nM chemokineMCP-1 protein for CCR2 assay or 50 nm chemokine TECK protein for CCR9assay) placed at the lower chamber. Following an incubation at 37° C.(90-minute for CCR2; 150-minute for CCR9), during which cells migratedagainst the chemokine gradient, the assay was terminated by removing thecell drops from atop the filter. To quantify cells migrated across themembrane, 5 μL of 7× CyQUANT® solution was added to each well in thelower chamber, and the fluorescence signal measured on a SpectrafluorPlus fluorescence plate reader (TECAN, Durham, N.C.). The degree ofinhibition was determined by comparing migration signals betweencompound-treated and untreated cells. IC₅₀ calculation was furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

BiRAM Assay

The primary screen to identify chemokine antagonists was carried outusing BiRAM assay (WO 02101350, US2004023286), which detects potentialhits by their ability to activate cell migration under inhibitorychemokine concentration. To begin such an assay, chemokine expressingcells (such as THP-1 cells for CCR2 assay or MOLT-4 cells for CCR9assay) were harvested by centrifugation of cell suspension at 1000 RPMon a GS-6R Beckman centrifuge. The cell pellet was resuspended inchemotaxis buffer (HBSS/0.1% BSA) at 10×10⁶ cells/mL for CCR2 assay(5×10⁶ cells/mL for CCR9 assay). Twenty-five microliters of cells wasmixed with an equal volume of a test compound diluted to 20 μM in thesame buffer. Twenty microliters of the mixture was transferred onto thefilter in the upper chemotaxis chamber, with 29 μL of chemokine solutioncontaining chemokine ligand (100 nM chemokine MCP-1 and MIP-1α proteinfor CCR2 assay or 500 nm chemokine TECK protein for CCR9 assay) wasplaced in the lower chamber. Following an incubation at 37° C.(90-minute for CCR2; 150-minute for CCR9), the assay was terminated byremoving the cell drops from atop the filter. To quantify cells migratedacross the membrane, 5 μL of 7× CyQUANT® solution was added to each wellin the lower chamber, and the fluorescence signal measured on aSpectrafluor Plus fluorescence plate reader (TECAN, Durham, N.C.).

For selection of potential hits, the level of migration activation wascalculated as a RAM index—the ratio between the signal of a particularwell and the median signal of the whole plate. Compounds with a RAMindex of greater than 1.5 for CCR2 assay (1.8 for CCR9 assay) wereregarded as RAM positive, and were selected for IC₅₀ determinations inconventional functional assays.

Calcium Flux Assay

Calcium flux assay measures an increase in intracellular calciumfollowing ligand-induced receptor activation. In the screen of chemokineantagonists, it was used as a secondary assay carried out on a FLIPR®machine (Molecular Devices, Mountain View, Calif.). To begin an assay,chemokine expressing cells (such as THP-1 cells for CCR2 assay or MOLT-4cells for CCR9 assay) were harvested by centrifugation of cellsuspension, and resuspended to 1.5×10⁶ cells/mL in HBSS (with 1% fetalcalf serum). Cells were then labeled with a calcium indicator dye Fluo-4AM for 45 minutes at 37° C. with gentle shaking. Following incubation,cells were pelletted, washed once with HBSS and resuspended in the samebuffer at a density of 1.6×10⁶ cells/mL. One hundred microliters oflabeled cells were mixed with 10 μL of test compound at the appropriateconcentrations on an assay plate. Chemokine protein (MCP-1 at a finalconcentration of 0.1 nM for CCR2 assay or TECK at a final concentrationof 25 nM for CCR9 assay) to activate the receptor. The degree ofinhibition was determined by comparing calcium signals betweencompound-treated and untreated cells. IC₅₀ calculations were furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

Ligand Binding Assay

Ligand binding assay was used to determine the ability of potential CCR2antagonists to block the interaction between CCR2 and its ligand MCP-1.CCR2 expressing THP-1 cells were centrifuged and resuspended in assaybuffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, andwith 0.2% bovine serum albumin) to a concentration of 2.2×10⁵ cells/mL.Binding assays were set up as follows. First, 0.09 mL of cells (1×10⁵THP-1 cells/well) was added to the assay plates containing thecompounds, giving a final concentration of ˜2-10 μM each compound forscreening (or part of a dose response for compound IC₅₀ determinations).Then 0.09 mL of ¹²⁵I labeled MCP-1 (obtained from Amersham; Piscataway,N.J.) diluted in assay buffer to a final concentration of ˜50 pM,yielding ˜30,000 cpm per well, was added, the plates sealed andincubated for approximately 3 hours at 4° C. on a shaker platform.Reactions were aspirated onto GF/B glass filters pre-soaked in 0.3%polyethyleneimine (PEI) solution, on a vacuum cell harvester (PackardInstruments; Meriden, Conn.). Scintillation fluid (50 μL; Microscint 20,Packard Instruments) was added to each well, the plates were sealed andradioactivity measured in a Top Count scintillation counter (PackardInstruments). Control wells containing either diluent only (for totalcounts) or excess MCP-1 (1 μg/mL, for non-specific binding) were used tocalculate the percent of total inhibition for compound. The computerprogram Prism from GraphPad, Inc. (San Diego, Calif.) was used tocalculate IC₅₀ values. IC₅₀ values are those concentrations required toreduce the binding of labeled MCP-1 to the receptor by 50%.

Discovery of Chemokine Antagonists

The discovery of chemokine antagonists was carried out in two steps:First, BiRAM assay was used to screen a compound library in ahigh-throughput manner. The assay detected compounds by their ability tocause a positive migration signal under BiRAM condition. Secondly, BiRAMpositive compounds were tested to determine their IC₅₀ values using theconventional migration, calcium flux assays and ligand binding assays.

For instance, in a screen of approximately 100,000 compounds, 2000individual wells representing approximately 2% of total compounds showeda desired RAM index (greater than 1.5 for CCR2; greater than 1.8 forCCR9). These compounds were cheery-picked and retested in duplicatewells by RAM assay. A total of 156 compounds were confirmed BiRAMpositives.

Since a BiRAM positive signal indicates only the presence of a receptorantagonist and not how strongly it blocks receptor functions, the BiRAMpositive compounds were further tested for potency in conventionalmigration, calcium flux and ligand binding assays. IC₅₀ determinationson this subset discovered several compounds with an IC₅₀ less than 1 μMand that did not inhibit other chemokine receptors examined atsignificant levels.

In Vivo Efficacy

A 17-day study of type II collagen-induced arthritis is conducted toevaluate the effects of a modulator on arthritis-induced clinical ankleswelling. Rat collagen-induced arthritis is an experimental model ofpolyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham et al., J. Exp. Med.,146(3):857-868 (1977), Bendele et al., Toxicologic Pathol., 27:134-142(1999), Bendele et al., Arthritis Rheum., 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17-day study. The test modulator isdosed daily by sub-cutaneous injection from day 9 to day 17 at a dose of100 mg/kg and a volume of 1 mL/kg in the following vehicle (24.5%Cremaphore EL, 24.5% common oil, 1% Benzylalcohol and 50% Distilledwater). Caliper measurements of the ankle joint diameter are takendaily, and reducing joint swelling is taken as a measure of efficacy.

The MDR1a-knockout mice, which lack the P-glycoprotein gene,spontaneously develop colitis under specific pathogen-free condition.The pathology in these animals has been characterized as Th1-type Tcell-mediated inflammation similar to ulcerative colitis in humans.Disease normally begins to develop at around 8-10 weeks after birth.However the ages at which disease emerges and the ultimate penetrancelevel often vary considerably among different animal facilities.

In a study using the MDR1a-knockout mice, a CCR9 antagonist is evaluatedby prophylactic administration for its ability to delay disease onset.Female mice (n=34) are dosed with 50 mg/kg twice a day by subcutaneousinjections for 14 consecutive weeks starting at age 10 weeks. The studyis evaluated for IBD-associated growth retardation.

Evaluation of a Test Modulator in a Rat Model of Thioglycollate-InducedPeritoneal Inflammation

A 2-day study of thioglycollate-induced inflammation is conducted toevaluate the effects of the test modulator. The hallmarks of this modelare reliable onset and progression of robust, easily measurableinflammatory cellular infiltrate. For the induction of inflammatoryperitonitis in Lewis rats, Brewer-Thioglycollate (1.0 mL, 4% solution indistilled water) is injected intra peritoneal (i.p.). Before thisinjection, the treatment group received test modulator or vehicle andthe control group received the same volume of PBS as i.p. injection.After 2 days, a peritoneal lavage as performed with ice-cold PBScontaining 1 mM EDTA. The recovered cells are counted with a cellcounter (Coulter Counter; Coulter Pharmaceutical, Palo Alto, Calif.) andmonocytes/macrophages were identified by flow cytometry usinglight-scatter properties.

Evaluation of a Test Modulator in a Mouse Model of Bacterial Infection

A 1-day study of streptococcus pneumoniae infection is conducted toevaluate the effects of the test modulator. The model measures bacterialinfection and spread in an animal following pulmonary infection withlive bacterial cultures, measured by inflammatory cellular infiltrate,and assessment of bacterial burden. C57/B6 mice are inoculated intranasally with LD50 400 CFU at day 0. Groups are either test modulator orvehicle control treated 1 day prior to bacterial inoculation and twicedaily throughout the study. Bacterial burden is measured at 24 hours byplating serial dilutions of homogenized lung tissue on agar plates andcounting colonies.

Pharmacologics to be Used in Conjunction with CCR2 Compounds

Pharmacological agents that can be used in conjunction with the CCR2antagonists of the current invention include those used for thetreatments of atherosclerosis, restenosis, multiple sclerosis, pulmonaryfibrosis, inflammatory bowel disease, rheumatoid arthritis,graft-versus-host disease, renal fibrosis, psoriasis, transplantationrejection, obesity, diabetes, hypercholesterolemia and cancer.

In the tables below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for either or both of the chemotaxis assay and/or calciummobilization assays, described above. TABLE 3 Compounds with CCR2activity in one of the chemotaxis, binding or calcium mobilizationassays, with IC50 < 1000 nM.

TABLE 4 Compounds with CCR9 activity in one of the chemotaxis, bindingor calcium mobilization assays, with IC50 < 1000 nM

It is therefore intended that the foregoing detailed description beregarded as illustrative rather than limiting, and that it be understoodthat it is the following claims, including all equivalents, that areintended to define the spirit and scope of this invention.

1. A compound of the formula (I), or a salt thereof:

wherein Ar is selected from the group consisting of substituted orunsubstituted C₆₋₁₀ aryl and substituted or unsubstituted 5- to10-membered heteroaryl; Y¹ is selected from the group consisting of—CR^(3a)—, —N—, and —N⁺(O)⁻—; Y² is selected from the group consistingof —CR^(3b)—, —N—, and —N⁺(O)⁻—; Y³ is selected from the groupconsisting of —CR^(3c)—, —N—, and —N⁺(O)⁻—; Y⁴ is selected from thegroup consisting of —CR^(3d)—, —N—, and —N⁺(O)⁻—; wherein at least oneof Y¹, Y², Y³, or Y⁴ is —N—. R^(3a), R^(3b), R^(3c), and R^(3d) are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —C(O)R⁴, —CO₂R⁴, —C(O)NR⁴R⁵, —OR⁴, —OC(O)R⁴, —OC(O)NR⁴R⁵, —SR⁴,—S(O)R⁴, —S(O)₂R⁴, —S(O)₂NR⁴R⁵, —NO₂, —NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)OR⁵,—NR⁴S(O)₂R⁵, —NR⁴C(O)NR⁵R⁶, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl; R⁴, R⁵, and R⁶ are eachindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl; R⁴ and R⁵, R⁵ and R⁶ or R⁴ and R⁶ may, together with theatoms to which they are attached, form a substituted or unsubstituted5-, 6-, or 7-membered ring; R¹ is selected from the group consisting ofhydrogen, —C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂NR⁷R⁸,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl; R² is selected from the group consisting ofhydrogen, halogen, —CN, —C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷,—OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸,—NR⁷C(O)R⁸, —NR⁷C(O)OR⁸, —NR⁷S(O)₂R⁸, —NR⁷C(O)NR⁸R⁹, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl; and R⁷,R⁸, and R⁹ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; R⁷ and R⁸, R⁸ and R⁹ or R⁷ and R⁹ may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring; and where R¹ and R² may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring; with the proviso thatN-(1,1-dimethylethyl)-3-[2-[[[3-(5,5-dimethyl-3-octadecyl-2-thiazolidinyl)-4-hydroxyphenyl]sulfonyl]amino]-4-hydroxy-6-methylphenyl]-7-[[4-[ethyl[2-[(methylsulfonyl)amino]ethyl]amino]phenyl]imino)-7H-pyrazolo[5,1-c]-1,2,4-triazole-6-carboxamideis excluded from the scope of formula (I).
 2. The compound of claim 1,which is represented by formula (II) or salts thereof:

wherein Y⁵, Y⁶ and Y⁷ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, —C(O)R¹⁵, —CO₂R¹⁵, —C(O)NR¹⁵R¹⁶,—O¹⁵, —OC(O)R¹⁵, —OC(O)NR¹⁵R¹⁶, —SR¹⁵, —S(O)R¹⁵, —S(O)₂R¹⁵,—S(O)₂NR¹⁵R¹⁶, —NO₂, —NR¹⁵R¹⁶, —NR¹⁵C(O)R¹⁶, —NR¹⁵C(O)OR¹⁶,—NR¹⁵S(O)₂R¹⁶, —NR¹⁵C(O)NR¹⁶R¹⁷, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl; R¹⁵, R¹⁶ andR¹⁷ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; and R¹⁵ and R¹⁶, R¹⁶ and R¹⁷ or R¹⁵ and R¹⁷may, together with the atoms to which they are attached, form asubstituted or unsubstituted 5-, 6-, or 7-membered ring.
 3. The compoundof claim 1, which is represented by formula (III) or salts thereof:

wherein X¹, X², X³, X⁴, and X⁵ are each independently selected from thegroup consisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹,—OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NO₂, —NR¹⁸C(O)R¹⁹, —NR¹⁸C(O)NR¹⁹R²⁰,—NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸, —S(O)₂R¹⁸,—S(O)₂NR¹⁸R¹⁹, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; R¹⁸, R¹⁹ and R²⁰ are eachindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl; and R¹⁸ and R¹⁹, R¹⁹ and R²⁰ or R¹⁸ and R²⁰ may, togetherwith the atoms to which they are attached, form a substituted orunsubstituted 5-, 6-, or 7-membered ring;
 4. The compound of claim 1,which is represented by formula (IV), or salts thereof:

wherein X¹ and X² are each independently from the group consisting ofhalogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, —CO₂R¹⁸, —OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹,—NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —NO₂, and —SR¹⁸;Y⁶ is selected from the group consisting of halogen, —CN, —OR¹⁸, andsubstituted or unsubstituted C₁₋₈ alkyl; R¹ is selected from the groupconsisting of hydrogen, —C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —S(O)R⁷, —S(O)₂R⁷,—S(O)₂NR⁷R⁸, substituted or unsubstituted C₁₋₈ alkyl, C₁₋₈ substitutedor unsubstituted cycloalkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl; R² isselected from the group consisting of hydrogen, halogen, —CN, —C(O)R⁷,—CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷, —OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷,—S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)OR⁸,—NR⁷S(O)₂R⁸, —NR⁷C(O)NR⁸R⁹, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl; where R¹ and R² may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring; R⁷, R⁸, and R⁹ are eachindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl; R⁷ and R⁸, R⁸ and R⁹ or R⁷ and R⁹ may, together with theatoms to which they are attached, form a substituted or unsubstituted5-, 6-, or 7-membered ring; R¹⁸, R¹⁹ and R²⁰ are each independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₆₋₁₀ (aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,and substituted or unsubstituted 3- to 10-membered heterocyclyl; R¹⁸ andR¹⁹, R¹⁹ and R²⁰ or R¹⁸ and R²⁰ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.
 5. The compound of claim 1, which is represented byformula (V), or salts thereof:


6. The compound of claim 1, which is represented by formula (VI), orsalts thereof:


7. The compound of claim 1 which is represented by formula (VII), orsalts thereof:

wherein Z is 0, 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of halogen, substituted or unsubstituted C1-8 alkyl, andsubstituted or unsubstituted C1-8 alkoxy.
 8. The compound of claim 1wherein Y₆ is selected from the group consisting of halogen and methyl.9. The compound of claim 1 wherein X₁ and X₂ are independently selectedfrom the group consisting of hydrogen, halogen, substituted andunsubstituted C₁-C₄ alkyl, and OR¹⁸.
 10. The compound of claim 9 whereinX₁ is Cl and X₂ is CF₃.
 11. The compound of claim 10 wherein R¹ is C₁-C₄alkyl.
 12. The compound of claim 1 which is represented by formula(VIII), or salts thereof:


13. The compound of claim 12 which is represented by formula (IX), orsalts thereof:

wherein R³ and R⁴ are each independently hydrogen, unsubstituted orsubstituted C₁₋₈ alkyl, or R³ and R⁴ together with the carbon which theysubstitute form a 3-10 membered carboxylic, 4-10 membered heterocyclicor 5-10 membered heteroaryl ring.
 14. The compound of claim 13 whereinR² is hydrogen.
 15. The compound of claim 1 which is represented byformula (XI), or salts thereof:

wherein X¹ and X² are each independently from the group consisting ofhalogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, —CO₂R¹⁸, —OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹,—NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —NO₂, and —SR¹⁸;Y⁶ is selected from the group consisting of halogen, —CN, —OR¹⁸, andsubstituted or unsubstituted C₁₋₈ alkyl; E is selected from the groupconsisting of O and NH; R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen, halogen, and substituted orunsubstituted C₁₋₈ alkyl; R² is selected from the group consisting ofhydrogen, halogen, —CN, —C(O)R⁷, —CO₂R⁷, —C(O)NR⁷R⁸, —OR⁷, —OC(O)R⁷,—OC(O)NR⁷R⁸, —SR⁷, —S(O)R⁷, —S(O)₂R⁷, —S(O)₂NR⁷R⁸, —NO₂, —NR⁷R⁸,—NR⁷C(O)R⁸, —NR⁷C(O)OR⁸, —NR⁷S(O)₂R⁸, —NR⁷C(O)NR⁸R⁹, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl; substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl; R⁷, R⁸,and R⁹ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl; R⁷ and R⁸, R⁸ and R⁹ or R⁷ and R⁹ may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring; R¹⁸, R¹⁹ and R²⁰ are eachindependently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl; R¹⁸ and R¹⁹, R¹⁹ and R²⁰ or R¹⁸ and R²⁰ may, together withthe atoms to which they are attached, form a substituted orunsubstituted 5-, 6-, or 7-membered ring.
 16. The compound of claim 14which is represented by formula (IX), or salts thereof wherein R² ishydrogen.
 17. A compound selected from the following: tert-butyl3-(3-(3-(4-tert-butylphenylsulfonamido)-5-methylpyridin-2-yl)-4H-1,2,4-triazol-4-yl)pyrrolidine-1-carboxylate;ethyl5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N-methyl-4H-1,2,4-triazole-3-carboxamide;N-(5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)acetamide;(S)-4-tert-butyl-N-(5-chloro-2-(4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;(S)-4-tert-butyl-N-(5-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;(S)-4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-(2-hydroxypropan-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-(isoxazol-5-yl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-methyl-2-(4-(1-methylpyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-methyl-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;ethyl5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxylate;ethyl5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-phenyl-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(3,4-dichlorophenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-N-isopropyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;5-(5-chloro-3-(4-methyl-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;(S)-4-chloro-N-(5-chloro-2-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;3,4-dichloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-((3S,4S)-4-methoxypyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(1-(dimethylamino)propan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(3-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(4-hydroxybutan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(4-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(5-fluoro-2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(morpholine-4-carbonyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(pyrrolidine-1-carbonyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-o-tolyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-((dimethylamino)methyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-(methoxymethyl)-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-cyclopropyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-(5-chloro-2-(5-isopropyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-bromopyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-methylpyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(4-(4-bromo-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(5-tert-butyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(5-bromo-4-(4-bromo-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-3,4-dichlorobenzenesulfonamide;N-(2-(5-bromo-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;N-(2-(5-bromo-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;andN-(5-bromo-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide.18. A method for treating a CCR2-mediated condition or disease or aCCR9-mediated condition or disease comprising administering to a subjectan effective amount of a compound of formula (I), or a salt thereof. 19.The method of claim 8, where the disease or condition is selected fromthe group consisting of atherosclerosis, restenosis, multiple sclerosis,inflammatory bowel disease, renal fibrosis, rheumatoid arthritis,obesity, diabetes, chronic obstructive pulmonary disease, idiopathicpulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis,transplantation rejection, graft-versus-host disease, cancer, andneuropathic pain.
 20. The method of claim 8, where the administering isoral, parenteral, rectal, transdermal, sublingual, nasal or topical. 21.The method of claim 8, further comprising administering ananti-inflammatory or analgesic agent.
 22. A method of modulating CCR2function in a cell, comprising contacting the cell with a CCR2modulating amount of the compound of claim
 1. 23. A method of modulatingCCR9 function in a cell, comprising contacting the cell with a CCR9modulating amount of the compound of claim
 1. 24. A method for treatinga CCR9-mediated condition or disease comprising administering to asubject an effective amount of the compound of claim
 1. 25. A method fortreating a CCR2-mediated condition or disease comprising administeringto a subject an effective amount of the compound of claim 1.